Compounds as PDE IV and TNF inhibitors

ABSTRACT

A compound of formula XIX 
                         
wherein R 1 , R 2 , Z 1 , Z 2 , Q 1 , Q 2  and Q 3  as defined in the specification.

This application is a continuation of U.S. patent application Ser. No.11/290,322, filed Nov. 30, 2005, now abandoned, which was a division ofU.S. patent application Ser. No. 10/792,579, filed Mar. 3, 2004, nowU.S. Pat. No. 7,045,660, issued May 16, 2006 which was a continuation ofU.S. application Ser. No. 10/207,493, filed Jul. 29, 2002, nowabandoned, which was a continuation of U.S. application Ser. No.08/592,817, filed Jan. 26, 1996, now U.S. Pat. No. 6,472,412, issuedOct. 29, 2002 which was a continuation-in-part of InternationalApplication No. PCT/GB94/01630 (designating the United States), filedJul. 28, 1994, which, in turn, was entitled to the benefit of priorfiled applications GB 9315581.0, filed Jul. 28, 1993 and GB 9315632.1,filed Jul. 28, 1993. The above-identified disclosures are incorporatedherein by reference.

FIELD OF THE INVENTION

This invention is directed to [di(ether or thioether)heteroaryl orfluoro substituted aryl] compounds, their preparation, pharmaceuticalcompositions containing these compounds, and their pharmaceutical use inthe treatment of disease states associated with proteins that mediatecellular activity.

Disease states associated with abnormally high physiological levels ofcytokines such as TNF are treatable according to the invention. TNF isan important pro-inflammatory cytokine which causes hemorrhagic necrosisof tumors and possesses other important biological activities. TNF isreleased by activated macrophages, activated T-lymphocytes, naturalkiller cells, mast cells and basophils, fibroblasts, endothelial cellsand brain astrocytes among other cells.

The principal in vivo actions of TNF can be broadly classified asinflammatory and catabolic. It has been implicated as a mediator ofendotoxic shock, inflammation of joints and of the airways, immunedeficiency states, allograft rejection, and in the cachexia associatedwith malignant disease and some parasitic infections. In view of theassociation of high serum levels of TNF with poor prognosis in sepsis,graft versus host disease and acute respiratory distress syndrome, andits role in many other immunological processes, this factor is regardedas an important mediator of general inflammation.

TNF primes or activates neutrophils, eosinophils, fibroblasts andendothelial cells to release tissue damaging mediators. TNF alsoactivates monocytes, macrophages and T-lymphocytes to cause theproduction of colony stimulating factors and other pro-inflammatorycytokines such IL₁, IL₆, IL₈ and GM-CSF, which in some case mediate theend effects of TNF. The ability of TNF to activate T-lymphocytes,monocytes, macrophages and related cells has been implicated in theprogression of Human Immunodeficiency Virus (HIV) infection. In orderfor these cells to become infected with HIV and for HIV replication totake place the cells must be maintained in an activated state. Cytokinessuch as TNF have been shown to activate HIV replication in monocytes andmacrophages. Features of endotoxic shock such as fever, metabolicacidosis, hypotension and intravascular coagulation are thought to bemediated through the actions of TNF on the hypothalamus and in reducingthe anti-coagulant activity of vascular endothelial cells. The cachexiaassociated with certain disease states is mediated through indirecteffects on protein catabolism. TNF also promotes bone resorption andacute phase protein synthesis.

The discussion herein related to disease states associated with TNFinclude those disease states related to the production of TNF itself,and disease states associated with other cytokines, such as but notlimited to IL-1, or IL-6, that are modulated by association with TNF.For example, an IL-1 associated disease state, where IL-1 production oraction is exacerbated or secreted in response to TNF, would therefore beconsidered a disease state associated with TNF. TNF-alpha and TNF-betaare also herein referred to collectively as “TNF” unless specificallydelineated otherwise, since there is a close structural homology betweenTNF-alpha (cachectin) and TNF-beta (lymphotoxin) and each of them has acapacity to induce similar biologic responses and bind to the samecellular receptor.

Disease states associated with pathological conditions that aremodulated by inhibiting enzymes, which are associated with secondarycellular messengers, such as cyclic AMP phosphodiesterase, are alsotreatable according to the invention Cyclic AMP phosphodiesterase is animportant enzyme which regulates cyclic AMP levels and in turn therebyregulates other important biological reactions. The ability to regulatecyclic AMP phosphodiesterase, including type IV cyclic AMPphosphodiesterase, therefore, has been implicated as being capable oftreating assorted biological conditions.

In particular, inhibitors of type IV cyclic AMP phosphodiesterase havebeen implicated as being bronchodilators and asthma-prophylactic agentsand as agents for inhibiting eosinophil accumulation and of the functionof eosinophils, and for treating other diseases and conditionscharacterized by, or having an etiology involving, morbid eosinophilaccumulation. Inhibitors of cyclic AMP phosphodiesterase are alsoimplicated in treating inflammatory diseases, proliferative skindiseases and conditions associated with cerebral metabolic inhibition.

Reported Developments

Chemical Abstracts, 108(15), Apr. 11, 1988, abstract no. 131583ppertains to an abstract of Japanese Patent Application Publication No.JP-A-62 158,253 which discloses that a substituted phenyl compound offormula

is a cardiotonic, but does not disclose or suggest that the compoundinhibits cyclic AMP phosphodiesterase or TNF. JP-A-62 158,253 also doesnot disclose or suggest that the moiety that is ortho to R¹ may beanything other than benzyloxy. JP-A-62 158,253 furthermore does notdisclose compounds wherein a methine (═CH—) moiety of the phenyl moietyof the benzamido moiety is substituted by a halomethine (═CX—; wherein Xis a halo atom) moiety or an imine (═N—) moiety.

Chemical Abstracts, 99(6), Aug. 8, 1983, abstract no. 43556z pertains toan abstract of Japanese Patent Application Publication No. JP-A-5869,812 which discloses that a phenyl compound of formula

is a hypoglycemic agent, but does not disclose or suggest that thecompound inhibits cyclic AMP phosphodiesterase or TNF. JP-A-5 869,812also does not disclose or suggest that the benzamido moiety may besubstituted by anything other than methoxy.

Panos Grammaticakis, Bull. Soc. Chim. Fr., 848-857 (1965) discloses aphenyl compound of the formula

Grammaticakis examines the ultraviolet and visible absorbances ofcompounds bearing different substituents. Grammaticakis does notdisclose or suggest that the compound exhibits any pharmacologicalactivity. JP-A-5 869,812 also does not disclose or suggest that thebenzamido moiety may be substituted by anything other than methoxy.

Ian W. Mathison, et al., J. Med. Chem., 16(4), 332-336 (1973), disclosesthat a phenyl compound of formula

is a hypotensive agent, but do not disclose or suggest that the compoundinhibits cyclic AMP phosphodiesterase or TNF. Mathison, et al., also donot disclose or suggest that the benzamido moiety may be substituted byanything other than methoxy.

European Patent Application Publication No. EP 232199 B1 discloses thatphenyl compounds of formula

wherein R² is alkyl or mono- or polycyclic cycloalkyl, exhibitanti-inflammatory and/or anti-allergic activity. EP 232199 B1 does notdisclose or suggest compounds wherein the R² substituent is bonded tothe phenyl moiety via an oxygen or sulfur atom. EP 232199 B1 furthermoredoes not disclose compounds wherein a methine moiety of the phenylmoiety of the benzamido moiety is substituted by a halomethine moiety oran imine moiety.

European Patent Application Publication No. EP 470,805 A1 disclosesphenyl compounds of the formula

wherein R may be C₃₋₇ alkyl, C₃₋₇ cycloalkyl or

Z may be a bond; o is 1-4; a and b are independently 1-3; and c is 0-2.EP 470,805 A1 discloses that these compounds are useful intermediatesfor preparing PDE IV inhibitors, but does not disclose or suggest thatthe compounds have any pharmacological activity. EP 470,805 A1furthermore does not disclose compounds wherein a methine moiety of thephenyl moiety of the phenylacyl moiety is substituted by a halomethinemoiety or an imine moiety.

Japanese Patent Application Publication No. JP-A-0 4360847 disclosescompounds of the formula

wherein R¹, R² and R³ may be the same or different and may be halo orlower alkoxy or lower alkyl both optionally substituted by halo; and Amay be optionally substituted aryl or 5-6 membered heterocyclyl group.JP-A-0 4360847 discloses that the compounds are useful intermediates forpreparing antimicrobial agents, but does not disclose or suggest thatthe compounds have any pharmacological activity. JP-A-0 4360847 alsodoes not disclose that the compounds wherein the phenylacyl moiety issubstituted in the 3,4 positions relative to the acyl moiety by loweralkoxy groups and has a methine moiety of the phenyl moiety substitutedby a halomethine moiety or an imine moiety.

WO Patent Application No. 92/12961 discloses that compounds of theformula

inhibit cyclic AMP phosphodiesterase. WO Patent Application No. 92/12961does not disclose or suggest that these compound inhibit TNF. WO PatentApplication No. 92/12961 also does not disclose compounds wherein amethine moiety of the diether phenyl moiety is substituted by ahalomethine moiety or an imine moiety.

WO Patent Application No. 93/25517 discloses that compounds of thefollowing formula inhibit PDE IV. WO Patent Application No. 93/25517does

not disclose or suggest that these compound inhibit TNF. WO PatentApplication No. 93/25517 also does not disclose compounds wherein amethine moiety of the diether phenyl moiety is substituted by ahalomethine moiety or an imine moiety.

WO Patent Application No. 93/10228 discloses that compounds of thefollowing formula inhibit PDE IV and as such are useful in treatment ofinflammatory diseases. WO Patent Application No. 93/10228 does notdisclose or suggest

that these compounds inhibit TNF. WO Patent Application No. 93/10228also does not disclose compounds wherein a methine moiety of the dietherphenyl moiety is substituted by a halomethine moiety or an imine moiety.

WO Patent Application No. 93/07111 discloses that compounds of thefollowing formula wherein X may be YR₂; Y is C or S(O)_(m); X₃ ishalogen or

hydrogen; and A is a group of formula

inhibit PDE IV. WO Patent Application No. 93/07111 does not disclose orsuggest compounds wherein the A substituent is a [(—CXNH— or—CXCH₂—)aryl or heteroaryl] moiety wherein X is O or S.

WO Patent Application No. 91/16303 discloses that compounds of thefollowing formula wherein R₁, R₂ and R₃ may be hydrogen, halogen, loweralkyl,

lower alkoxy or cycloalkoxy inhibit PDE IV. WO Patent Application No.91/16303 does not disclose or suggest compounds wherein the lactammoiety is substituted by a [(—CXNH— or —CXCH₂—)aryl or heteroaryl]moiety wherein X is O or S.

WO Patent Application No. 92/19594 discloses that compounds of thefollowing formula wherein X may be YR₂; Y is O or S(O)_(m); and X₃ maybe

hydrogen or halogen inhibit PDE IV. WO Patent Application No. 92/19594does not disclose or suggest compounds wherein the lactam moiety issubstituted by a [(—CXNH— or —CXCH₂—)aryl or heteroaryl] moiety whereinX is O or S.

SUMMARY OF THE INVENTION

This invention is directed to a compound of formula I, which is usefulfor inhibiting the production or physiological effects of TNF in thetreatment of a patient suffering from a disease state associated with aphysiologically detrimental excess of tumor necrosis factor (TNF), whereformula I is as follows:

wherein

R¹ is lower alkyl optionally substituted by one or more of halo,cycloalkyl or cycloalkenyl;

R² is alkyl, alkenyl or alkynyl each optionally substituted by one ormore of halo, cycloalkyl or cycloalkenyl; or cycloalkyl or cycloalkenyleach optionally substituted by one or more of halo, methylidene oralkyl; or optionally substituted cyclothioalkyl consisting of anon-aromatic monocyclic or multicyclic ring system of 3 to about 10 ringatoms wherein at least one of the ring atoms is sulphur and the otherring atoms are carbon and the substituted cyclothioalkyl is substitutedby one or more halo, or any ring sulphur atom is optionally oxidised tothe corresponding S-oxide or S,S-dioxide; or optionally substitutedcyclothioalkenyl consisting of a non-aromatic monocyclic or multicyclicring system of 3 to about 10 ring atoms wherein at least one of the ringatoms is sulphur, the other ring atoms are carbon and the ring systemcontains a carbon-carbon double bond and the substitutedcyclothioalkenyl is substituted by one or more halo or any ring sulphuratoms is optionally oxidised to the corresponding S-oxide orS,S-dioxide;

R³ is optionally substituted aryl or heteroaryl, wherein the substitutedaryl or substituted heteroaryl group is substituted by one or moresubstituents which may be the same or different and are selected fromalkyl, aryl, aralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy,aralkyloxy, carboxy, acyl, aroyl, halo, nitro, cyano, carboxy,alkoxycarboxyl, aryloxycarbonyl, aralkyloxycarbonyl, acylamino,aroylamino, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl,alkylthio, arylthio, aralkylthio, Y¹Y²N—, Y¹Y²NCO— or Y¹Y²NSO₂—, whereY¹ and Y² are independently hydrogen, alkyl, aryl, and aralkyl;

Q¹, Q² and Q³ are independently nitrogen, CX or CH, provided that atleast one of Q¹, Q² and Q³ is other than CH;

Z, Z¹ and Z² are independently oxygen or sulfur;

Z³ is —CH═CH—, —CZCH₂—, —CZ-CZ-, —CH₂—NH—, —CH₂—O—, —CX₂—O—, —CH₂—S—,—CH₂—SO₂— or —CZNH—; and

X is halo;

or N-oxide thereof or a pharmaceutically acceptable salt thereof; withthe proviso that R¹Z¹ and R²Z² cannot both represent methoxy.

Compounds within the scope of the present invention also inhibit cyclicAMP phosphodiesterase, and are useful in treating a disease stateassociated with pathological conditions that are modulated by inhibitingcyclic AMP phosphodiesterase, such disease states including inflammatoryand autoimmune diseases, in particular type IV cyclic AMPphosphodiesterase. The present invention is therefore directed to theirpharmacological use, pharmacological compositions comprising thecompounds and methods for their preparation.

DETAILED DESCRIPTION OF THE INVENTION

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings:

Definitions

“Patient” includes both human and other mammals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched having about 1 to about 15 carbon atoms in the chain. Preferredalkyl groups have 1 to about 12 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl are attached to a linear alkyl chain. “Lower alkyl” means about 1to about 4 carbon atoms in the chain which may be straight or branched.The alkyl group is optionally substituted by one or more of halo,cycloalkyl or cycloalkenyl groups. Exemplary alkyl groups includemethyl, fluoromethyl, difluoromethyl, trifluoromethyl,cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl anddodecyl; preferred are methyl, difluoromethyl and i-propyl.

“Alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and Which may be straight or branched havingabout 2 to about 15 carbon atoms in the chain. Preferred alkenyl groupshave 2 to about 12 carbon atoms in the chain; and more preferably about2 to about 4 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl or propyl are attached to alinear alkenyl chain. “Lower alkenyl” means about 2 to about 4 carbonatoms in the chain which may be straight or branched. The alkenyl groupis optionally substituted by one or more halo, cycloalkyl orcycloalkenyl. Exemplary alkenyl groups include ethenyl, propenyl,n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyland decenyl.

“Alkynyl” means an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which may be straight or branched havingabout 2 to about 15 carbon atoms in the chain. Preferred alkynyl groupshave 2 to about 12 carbon atoms in the chain; and more preferably about2 to about 4 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl or propyl are attached to alinear alkynyl chain. “Lower alkynyl” means about 2 to about 4 carbonatoms in the chain which may be straight or branched. The alkynyl groupis optionally substituted by one or more halo, cycloalkyl orcycloalkenyl. Exemplary alkynyl groups include ethynyl, propynyl,n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl anddecynyl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring system ofabout 3 to about 10 carbon atoms. The cycloalkyl group is optionallysubstituted by one or more halo, methylidene (H₂C═) or alkyl. Exemplarymonocyclic cycloalkyl rings include cyclopentyl, fluorocyclopentyl,cyclohexyl and cycloheptyl; more preferred is cyclopentyl. Exemplarymulticyclic cycloalkyl rings include 1-decalin, adamant-(1- or 2-)yl,trinorbornyl and tricyclo[2.2.1.0^(2.6.)]heptyl.

“Cycloalkenyl” means a non-aromatic monocyclic or multicyclic ringsystem containing a carbon-carbon double bond and having about 3 toabout 10 carbon atoms. The cycloalkenyl group is optionally substitutedby one or more halo, alkyl and methylidene (CH₂═). Preferred monocycliccycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl;more preferred is cyclopentenyl. A preferred multicyclic cycloalkenylring is a norbornylenyl.

“Cyclothioalkyl” means a non-aromatic monocyclic or multicyclic ringsystem of about 3 to about 10 ring atoms wherein at least one of thering atoms is sulfur and the other ring atoms are carbon. Preferredrings include about 5 to about 6 ring atoms. Also preferred are rings inwhich one or two of the ring atoms is/are sulfur. The cyclothioalkyl isoptionally substituted by one or more halo. The thio moiety of thecyclothioalkyl ring may also be optionally oxidized to the correspondingS-oxide or S,S-dioxide. Preferred monocyclic cyclothioalkyl ringsinclude tetrahydrothiophenyl and tetrahydrothiopyranyl; more preferredis tetrahydrothiophenyl.

“Cyclothioalkenyl” means a non-aromatic monocyclic or multicyclic ringsystem having about 3 to about 10 ring atoms wherein at least one of thering atoms is sulfur and the other ring atoms are carbon and the ringsystem contains a carbon-carbon double bond. Preferred rings includeabout 5 to about 6 ring atoms. Also preferred are rings in which one ortwo of the ring atoms is/are sulfur. The cyclothioalkenyl is optionallysubstituted by one or more halo. The thio moiety of the cyclothioalkenylmay also be optionally oxidized to the corresponding S-oxide orS,S-dioxide. Preferred monocyclic cyclothioalkyl rings includedihydrothiophenyl and dihydrothiopyranyl; more preferred isdihydrothiophenyl.

“Aromatic” means aryl or heteroaryl as defined below. Preferred aromaticgroups include phenyl, halo substituted phenyl and azaheteroaryl.

“Aryl” means aromatic carbocyclic radical containing about 6 to about 10carbon atoms. Exemplary aryl include phenyl or naphthyl, or phenyl ornaphthyl substituted with one or more aryl group substituents which maybe the same or different, where “aryl group substituent” includeshydrogen, alkyl, aryl, aralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy,aralkyloxy, carboxy, acyl, aroyl, halo, nitro, cyano, carboxy,alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, acylamino,aroylamino, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl,alkylthio, arylthio, aralkylthio, Y¹Y²N—, Y¹Y²NCO— or Y¹Y²NSO₂—, whereY¹ and Y² are independently hydrogen, alkyl, aryl, and aralkyl.Preferred aryl group substituents include hydrogen, alkyl, hydroxy,acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio,Y³Y⁴N—, Y³Y⁴NCO— and Y³Y⁴NSO₂—, where Y³ and Y⁴ are independentlyhydrogen and alkyl.

“Heteroaryl” means about a 5- to about a 10-membered aromatic monocyclicor multicyclic hydrocarbon ring system in which one or more of thecarbon atoms in the ring system is/are element(s) other than carbon, forexample nitrogen, oxygen or sulfur. The heteroaryl may also besubstituted by one or more aryl group substituents. “Azaheteroaryl”means a subclass of heteroaryl wherein one or more of the atoms in thering system is/are replaced by nitrogen. Imine nitrogen moieties of anazaheteroaryl group may also be in an oxidized state such as thecorresponding N-oxide. Exemplary heteroaryl groups include pyrazinyl,furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl,pyridazinyl, 1,2,4-triazinyl, quinolinyl, and isoquinolinyl. Preferredheteroaryl groups include pyrazinyl, thienyl, pyridyl, pyrimidinyl,isoxazolyl and isothiazolyl. Preferred azaheteroaryl groups includepyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or 1,2,4-triazinyl.

“Aralkyl” means an aryl-alkyl-group in which the aryl and alkyl are aspreviously described. Preferred aralkyls contain a lower alkyl moiety.Exemplary aralkyl groups include benzyl, 2-phenethyl andnaphthlenemethyl.

“Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Exemplaryhydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

“Acyl” means an H—CO— or alkyl-CO— group in which the alkyl group is aspreviously described. Preferred acyls contain a lower alkyl. Exemplaryacyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl,butanoyl and palmitoyl.

“Aroyl” means an aryl-CO— group in which the aryl group is as previouslydescribed. Exemplary groups include benzoyl and 1- and 2-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Exemplary alkoxy groups include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy and heptoxy.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Exemplary aryloxy groups include phenoxy andnaphthoxy.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl groups is aspreviously described. Exemplary aralkyloxy groups include benzyloxy and1- or 2-naphthalenemethoxy.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Exemplary alkylthio groups include methylthio,ethylthio, i-propylthio and heptylthio.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Exemplary arylthio groups include phenylthio andnaphthylthio.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. An exemplary aralkylthio group is benzylthio.

“Y³Y⁴N—” means a substituted or unsubstituted amino group, wherein Y³and Y⁴ are as previously described. Exemplary groups include amino(H₂N—), methylamino, ethylmethylamino, dimethylamino and diethylamino.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Exemplary alkoxycarbonylgroups include methoxy- and ethoxycarbonyl.

“Aryloxycarbonyl” means an aryl-O—CO— group. Exemplary aryloxycarbonylgroups include phenoxy- and naphthoxycarbonyl.

“Aralkyloxycarbonyl” means an aralkyl-O—CO— group. An exemplaryaralkyloxycarbonyl group is benzyloxycarbonyl.

“Y¹Y²NCO—” means a substituted or unsubstituted carbamoyl group, whereinY¹ and Y² are as previously described. Exemplary groups are carbamoyl(H₂NCO—) and dimethylcarbamoyl (Me₂NCO—).

“Y¹Y²NSO₂—” means a substituted or unsubstituted sulfamoyl group,wherein Y¹ and Y² are as previously described. Exemplary groups aresulfamoyl (H₂NSO₂—) and dimethylsulfamoyl (Me₂NSO₂—).

“Acylamino” is an acyl-NH— group wherein acyl is as defined herein.

“Aroylamino” is an aroyl-NH— group wherein aroyl is as defined herein.

“Alkylsulfonyl” means an alkyl-SO₂— group. Preferred groups are those inwhich the alkyl group is lower alkyl.

“Alkylsulfinyl” means an alkyl-SO— group. Preferred groups are those inwhich the alkyl group is lower alkyl.

“Arylsulfonyl” means an aryl-SO₂— group.

“Arylsulfinyl” means an aryl-SO— group.

“Halo” means fluoro, chloro, bromo, or iodo. Preferred are fluoro,chloro or bromo; more preferred are fluoro or chloro, and furtherpreferred is fluoro.

“N-oxide” means a moiety of the following structure

Preferred Embodiments

A compound of formula I is preferred for use in treating a disease stateassociated with a physiologically detrimental excess of tumor necrosisfactor. Disease states associated with pathological conditions that aremodulated by inhibiting tumor necrosis factor are treatable with acompound of formula I.

A compound of formula I is also preferred for use in treating a diseasestate associated with a physiologically detrimental excess of cyclic AMPphosphodiesterase. Disease states associated with pathologicalconditions that are modulated by inhibiting cyclic AMP phosphodiesteraseare treatable with a compound of formula I.

According to a compound aspect of the invention, preferred compounds aredescribed formula I,

wherein

R² is alkyl, cycloalkyl, cycloalkenyl or cyclothioalkyl;

R³ is phenyl, substituted phenyl or azaheteroaryl;

Q¹ and Q² are independently nitrogen, CX or CH, and at least one of Q¹and Q² is other than CH;

Q³ is CH; and

Z³ is —CZCH₂— or —CZNH—.

According to a further compound aspect of the invention, preferredcompounds are described formula I,

wherein

R¹ is methyl or difluoromethyl;

R² is isopropyl, cyclopropylmethyl, cyclopentyl, trinorbornyl,trinorbornenyl, tricyclo[2.2.1.0^(2.6.)]heptanyl andtetrahydrothiophenyl;

Q³ is CH;

Z¹ is oxygen or sulphur;

Z² is oxygen; and

Z³ is —COCH₂— or —CONH—.

According to another aspect of the invention, more preferred compoundsof formula I are described wherein Q¹ and Q² are independently nitrogen,CX or CH, and at least one of Q¹ and Q² is nitrogen or CX, and Q³ is CH.Also preferred are compounds of the invention wherein Q¹ is CX, and Q²and Q³ are CH; Q² is CX, and Q¹ and Q³ are CH; Q¹ is N, and Q² and Q³are CH; Q² is N, and Q¹ and Q³ are CH; Q¹ and Q² are CH, and Q³ are N;and Q¹ and Q² are N, and Q³ are CH. CX is preferably CF. Furtherpreferred are compounds wherein Q² is nitrogen or CF.

According to a further aspect of the invention, preferred are N-oxidecompounds of formula I, that is compounds of formula I whereinindependently Q¹, Q² or Q³ is N-oxide and/or R³ is azaheterocyclylhaving an imine moiety thereof as an N-oxide. Further preferred arecompounds of formula I wherein Q¹ and Q³ are CH, and Q² is an N-oxide.Also further preferred are compounds of formula I wherein R³ is3,5-dihalo-1-oxido-4-pyridinium.

Compounds of the invention wherein R¹ is lower alkyl optionallysubstituted by one or more halo, preferably fluoro, are also preferred.Compounds of the invention wherein R² is substituted by one or morehalo, preferably fluoro, are also preferred. It is further preferredthat the halo substitution is on a position of R¹ or R² that is attachedrespectively to Z¹ and Z². Where R² is cyclothioalkyl orcyclothioalkenyl substituted by halo, it is also preferred that the halosubstitution is on a position adjacent to the thio moiety of thecyclothioalkyl or cyclothioalkenyl.

Among the compounds of the invention wherein R³ is substituted phenyl,the phenyl group is preferably substituted on the 2-position or on boththe 2- and 6-positions; more preferably on both the 2- and 6-positions.It is also preferred that the phenyl substituent is halo; preferablychloro or fluoro.

Similarly, among compounds of the invention where R³ is substitutedheteroaryl, the heteroaryl group is preferably substituted on one orboth, more preferably on both, of the positions adjacent to a positionof R³ that is attached to Z³.

Special embodiments of the compounds of the invention include those offormula I wherein R³ is azaheteroaryl substituted on one or both, morepreferably on both, of the positions adjacent to a position of R³ thatis attached to Z³, or an N-oxide thereof. Further preferred arecompounds wherein R³ is a 3,5-dihalopyrid-4-yl moiety, preferablywherein halo is chloro or fluoro, or an N-oxide thereof.

Special embodiments of the compounds of the invention also include thoseof formula I wherein Z³ is —CZNH— or —CZCH₂—, more preferably wherein Zis oxygen.

Special embodiments of the compounds of the present invention includethose wherein R² is isopropyl, cyclopropylmethyl, cyclopentyl,trinorbornyl, trinorbornenyl, tricyclo[2.2.1.0^(2.6.)]heptanyl andtetrahydrothiophenyl.

Another special embodiment of the compounds of the invention includethose of formula I wherein R¹ is lower alkyl optionally substituted byhalo, preferably fluoro; and R² is isopropyl, cyclopropylmethyl,cyclopentyl, trinorbornyl, trinorbornenyl,tricyclo[2.2.1.0^(2.6.)]heptanyl and tetrahydrothiophenyl.

According to a further aspect of the invention, preferred compounds offormula I are described wherein Z¹ and Z² are oxygen, and Z¹ is sulfurand Z² is oxygen are preferred. More preferred are where Z¹ and Z² areoxygen.

Preferred compounds for use according to the invention are selected fromthe following:

-   A    N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   B    N-(2,6-difluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   C    N-(2-chloro-6-fluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   D    N-(2-trifluoromethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   E    N-(2,4,6-trichlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   F    N-(2,6-dibromophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   G    N-(2-chloro-6-methylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   H    N-(2,6-dichlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   I N-(2-fluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   J N-phenyl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   K N-(2-methoxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   L N-(2-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   M N-(3-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N N-(4-methoxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   O    N-(2,6-dimethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   P    N-(2-methylthiophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   Q N-(2-bromophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   R    N-(2-methoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   S    N-(2-aminosulfonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   T N-(2-benzoylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   U N-(2-cyanophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   V    N-(2,5-dichlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   W N-(3-methylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   X N-(2-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   Y    N-(2-dimethylaminophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   Z N-(2-acetylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AA N-(2-hydroxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AB    N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AC N-pyrid-2-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AD N-pyrazin-2-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AE N-pyrimidin-2-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AF    N-(3-methylpyrid-2-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AG N-pyrid-3-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AH    N-(3-chloropyrid-2-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AI    N-(3-chloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AJ N-pyrid-4-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AK    N-(3,5-dimethylisoxazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AL    N-(3,5-dibromopyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AM    N-(3,5-dimethylpyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AN    N-(2,6-dichloro-4-cyanophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AO    N-(2,6-dichloro-4-methoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AP    N-(2,3,5-trifluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AQ    N-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AR    N-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AS    N-(3,5-difluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AT    N-(3-bromo-5-chloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AU    N-(2,4,6-trifluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AV    N-(2,6-dichloro-4-methoxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AW    N-(4,6-dichloropyrimid-5-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AX    N-(2,3,5,6-tetrafluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AY    N-(3,5-dichloro-2,6-difluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   AZ    N-(5-cyano-3-methylisothiazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   BA    N-(2,6-dichloro-4-carbamoylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   BB    N-(3-chloro-2,5,6-trifluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   BC N-(4-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   BD    N-(3-methyl-5-bromoisothiazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   BE    N-(3,5-dimethylisothiazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   BF    N-(2,6-difluorophenyl)-3-cyclohexyloxy-6-fluoro-4-methoxybenzamide;-   BG N-(2,6-difluorophenyl)-3-butoxy-6-fluoro-4-methoxybenzamide;-   BH N-(2,6-difluorophenyl)-3-propoxy-6-fluoro-4-methoxybenzamide;-   BJ    N-(3,5-dichloropyrid-4-yl)-3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzamide;-   BL    N-(3,5-dichloropyrid-4-yl)-3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzamide;-   BN    N-(2-methylsulfonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   BP    N-(2-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxy(thiobenzamide);-   BR    N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxy(thiobenzamide);-   BT    N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxy(thiobenzamide);-   BV    N-(2,6-dichloro-4-acetylaminophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   BX    N-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   BZ    N-(2,6-dichloro-4-formylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   CB sodium salt of    N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   CC    (±)N-(3,5-dichloropyrid-4-yl)-3-exonorbornyloxy-6-fluoro-4-methoxybenzamide;-   CD    N-(3,5-dichloropyrid-4-yl)-2-fluoro-5-isopropyloxy-4-methoxybenzamide;-   CE    (±)N-(3,5-dichloropyrid-4-yl)-2-fluoro-4-methoxy-5-(tricyclo[2.2.1.0]hept-2-yloxy)benzamide    hemihydrate;-   CF    N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-difluoromethoxy-6-fluorobenzamide-   CG    N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-2-fluoro-5-isopropyloxybenzamide;-   CH    2-(3,5-dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanone;-   CI    N-(3,5-dichloro-1-oxido-4-pyridinio)-2-fluoro-5-isopropyloxy-4-methoxybenzamide;-   CJ (±)    N-(3,5-dichloro-1-oxido-4-pyridinio)-3-exo(8,9,10-trinorbornyloxy)-6-fluoro-4-methoxybenzamide;-   CK    N-(3,5-dichloro-1-oxido-4-pyridinio)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   CL    N-(3,5-dichloro-1-oxido-4-pyridinio)-3-cyclopentyloxy-4-difluoromethoxy-6-fluorobenzamide;-   CM    N-(3,5-dichloro-1-oxido-4-pyridinio)-4-difluoromethoxy-2-fluoro-5-isopropyloxybenzamide;-   CN    2-(3,5-Dichloro-1-oxido-4-pyridinio)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanone;-   CO    5-cyclopentyloxy-N-(3,5-dichloropyrid-4-yl)-6-methoxynicotinamide;-   CP N-(2,6-dichlorophenyl)-5-cyclopentyloxy-6-methoxynicotinamide;-   CQ    5-cyclopentyloxy-N-(3,5-dimethylisoxazol-4-yl)-6-methoxynicotinamide-   CR 5-cyclopentyloxy-N-(3,5-difluoropyrid-4-yl)-6-methoxynicotinamide-   CS    6-cyclopentyloxy-N-(3,5-dichloropyrid-4-yl)-5-methoxypyridine-2-carboxamide;-   CT    1-(5-cyclopentyloxy-6-methoxypyridin-3-yl)-2-(3,5-dichloropyrid-4-yl)ethanone;-   CU    5-cyclopentyloxy-N-(3,5-dichloro-4-pyridyl)-6-methylthionicotinamide;-   CV    N-(3,5-dichloro-4-pyridyl)-5-isopropyloxy-6-methylthionicotinamide;-   CW    2-(3,5-dichloro-4-pyridyl)-1-(5-isopropyloxy-6-methylthio-3-pyridyl)ethanone;-   CX    1-(5-cyclopentyloxy-6-methoxypyrid-3-yl)-2-(3,5-dichloro-1-oxido-4-pyridinio)ethanone    hemihydrate;-   CY    (±)—N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-exo-(8,9,10-trinorborn-5-en-2-yloxy)nicotinamide;-   CZ    (±)—N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)nicotinamide    monohydrate;-   DA    N-(3,5-dichloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DB    N-(2,6-difluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DC    N-(2-chloro-6-fluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DD    N-(2-trifluoromethylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DE    N-(2,4,6-trichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DF    N-(2,6-dibromophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DG    N-(2-chloro-6-methylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DH    N-(2,6-dichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DI    N-(2-fluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DJ N-phenyl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DK    N-(2-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DL    N-(2-chlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DM    N-(3-chlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DN    N-(4-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DO    N-(2,6-dimethylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DP    N-(2-methylthiophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DQ    N-(2-bromophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DR    N-(2-methoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DS    N-(2-aminosulfonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DT    N-(2-benzoylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DU    N-(2-cyanophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DV    N-(2,5-dichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DW    N-(3-methylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DX    N-(2-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DY    N-(2-dimethylaminophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   DZ    N-(2-acetylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EA    N-(2-hydroxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EB    N-(4-chloropyrid-3-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EC N-pyrid-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   ED N-pyrazin-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EE    N-pyrimidin-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EF    N-(3-methylpyrid-2-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EG N-pyrid-3-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EH    N-(3-chloropyrid-2-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EI    N-(3-chloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EJ N-pyrid-4-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EK    N-(3,5-dimethylisoxazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EL    N-(3,5-dibromopyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EM    N-(3,5-dimethylpyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EN    N-(2,6-dichloro-4-cyanophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EO    N-(2,6-dichloro-4-methoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EP    N-(2,3,5-trifluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EQ    N-(2,6-dichloro-4-ethoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   ER    N-(2,6-dichloro-4-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   ES    N-(3,5-difluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   ET    N-(3-bromo-5-chloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EU    N-(2,4,6-trifluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EV    N-(2,6-dichloro-4-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EW    N-(4,6-dichloropyrimid-5-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EX    N-(2,3,5,6-tetrafluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EY    N-(3,5-dichloro-2,6-difluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   EZ    N-(5-cyano-3-methylisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   FA    N-(2,6-dichloro-4-carbamoylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   FB    N-(3-chloro-2,5,6-trifluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   FC    N-(4-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   FD    N-(3-methyl-5-bromoisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   FE    N-(3,5-dimethylisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   FF    N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   FG    1-(4-cyclopentyloxy-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanone;-   FH    (±)—N-(3,5-difluoropyrid-4-yl)-6-methoxy-5-exo(8,9,10-trinorborn-2-yloxy)nicotinamide;-   FI    (±)—N-(3,5-dichloropyridin-4-yl)-6-methoxy-5-exo(8,9,10-trinorborn-2-yloxy)nicotinamide;-   FJ    (±)—N-(3,5-dichloropyrid-4-yl)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxamide;-   FK    (±)—N-(3,5-difluoropyrid-4-yl)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxamide    hydrate;-   FL    (±)—N-(3,5-dichloropyridin-4-yl)-5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxamide;-   FM    N-(3,5-dichloropyridin-4-yl)-4-cyclopropylmethoxy-5-methoxypyridine-2-carboxamide;-   FN    N-(3,5-dichloropyridin-4-yl)-4-isopropyloxy-5-methoxypyridine-2-carboxamide;-   FO    (±)—N-(3,5-dichloro-1-oxido-4-pyridinio)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]-hept-2-yloxy)pyridine-2-carboxamide;-   FP    (±)—N-(3,5-difluoro-1-oxido-4-pyridinio)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]-hept-2-yloxy)pyridine-2-carboxamide;-   FQ    N-(3,5-dichloro-1-oxido-4-pyridinio)-4-isopropyloxy-5-methoxypyridine-2-carboxamide;-   FR    N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxypyridine-2-carboxamide    hemihydrate;-   FS    (±)—N-(3,5-dichloro-1-oxido-4-pyridinio)-5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxamide;-   FT    N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-methoxy-1-oxidopyridinium-2-carboxamide;-   FU    N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxy-1-oxidopyridinium-2-carboxamide;-   FV    N-(3,5-dichloro-1-oxido-4-pyridinio)-4-isopropyloxy-5-methoxy-1-oxidopyridinium-2-carboxamide;-   FW    1-(5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanone;-   FX    (±)-1-(5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanone;-   FY    1-(4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)-5-methoxypyridin-2-yl)-2-(3,5-dichloro-1-oxido-4-pyridinio)ethanone;-   FZ    N-(3,5-dichloropyridin-4-yl)-4-cyclopropylmethoxy-5-methoxy-1-oxidopyridinium-2-carboxamide;-   GA    N-(3,5-dichloropyridin-4-yl)-4-isopropyloxy-5-methoxy-1-oxidopyridinium-2-carboxamide;-   GB    N-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-methoxy-1-oxidopyridinium-2-carboxamide    hemihydrate;-   GD    N-(2-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzylamine;-   GE    N-(2-chlorophenyl)-4-cyclopentyloxy-5-methoxy-2-aminomethylpyridine;-   GG    trans-2-(2,6-dichlorophenyl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethene;-   GH    trans-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)-2-(2,6-difluorophenyl)ethene;-   GI    trans-2-(2,6-dichlorophenyl)-1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)ethene;-   GJ    trans-1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)-2-(2,6-difluorophenyl)ethene;-   GL    1-[(3-cyclopentyloxy-6-fluoro-4-methoxy)phenyl]-2-(pyrid-4-yl)ethane-1,2-dione;-   GM    1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)-2-(pyrid-4-yl)ethane-1,2-dione;-   GN    N-(3,5-dichloropyrid-4-yl)-5-cyclopentyloxy-6-methoxypyridazine-3-carboxamide;-   GO    N-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-difluoromethoxypyridine-2-carboxamide;-   GP    N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-difluoromethoxypyridine-2-carboxamide;-   GQ    N-(3,5-dichloropyrid-4-yl)-4-cyclopentyloxy-5-difluoromethoxy-1-oxidopyridium-2-carboxamide;-   GR    N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-difluoromethoxy-1-oxidopyridium-2-carboxamide;-   GS    1-(5-difluoromethoxy-4-(cyclopentyloxy)pyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanone;-   GT    1-(5-difluoromethoxy-4-(cyclopentyloxy)-1-oxido-2-pyridium)-2-(3,5-dichloropyridin-4-yl)ethanone;-   GU    1-(5-difluoromethoxy-4-(cyclopentyloxy)pyridin-2-yl)-2-(3,5-dichloro-1-oxido-4-pyridinio)ethanone;-   GV    1-(5-difluoromethoxy-4-(cyclopentyloxy)-1-oxido-2-pyridium)-2-(3,5-dichloro-1-oxido-4-pyridinio)ethanone;-   GW N-(3,5-dichloropyrid-4-yl)-5,6-dimethoxypyridazine-3-carboxamide;    and-   GX    1-(5,6-dimethoxypyridazine-3-pyridium)-2-(3,5-dichloropyridin-4-yl)ethanone.

Preferred compounds include A, CC, CD, CE, CF, CG, CH, CI, CJ, CK, CL,CM, CN, CO, CP, CQ, CR, CS, CT, CU, CV, CW, CX, CY, CZ, DA, DB, FF, FG,FH, FI, FJ, FK, FL, FM, FN, FO, FP, FQ, FR, FS, FT, FU, FV, FW, FX, FY,FZ, GA, GB, GN, GO, GP.

The letters A-GX are allocated to compounds for easy reference in thisspecification.

Compounds of formula I may be prepared by the application or adaptationof known methods, by which is meant methods used heretofore or describedin the literature.

Thus, compounds of formula I wherein R¹, R², R³, Q¹, Q², Q³, Z¹ and

Z² are as hereinbefore defined, Z³ represents a —CZNH— linkage, and Z isoxygen, may be prepared by the reaction of compounds of formula II

wherein R¹, R², Z¹, Z², Q¹, Q² and Q³ are as hereinbefore defined and Xrepresents halo, such as bromo or, preferably, chloro, with a compoundof the formula III wherein R³ is as hereinbefore defined, preferably inthe presence ofR³NH₂  IIIa base such as an alkali metal hydride, such as sodium hydride, or anamine, preferably a tertiary amine, such as triethylamine or pyridine,optionally in an inert solvent, for example dichloromethane,dimethylformamide, or an ether, such as diethyl ether ortetrahydrofuran, preferably at a temperature from about 0° C. to thereflux temperature or at the melting point of the reaction mixture.

Alternatively, compounds of formula I wherein R¹, R², R³, Q¹, Q², Q³, Z¹and Z² are as hereinbefore defined, Z³ represents a —CZNH— linkage, andZ represents oxygen, may be prepared by the reaction of compounds offormula II as hereinbefore described, with a compound of the formula IVwherein R³R⁴CONHR³  IVis as hereinbefore defined, and R⁴ represents an alkyl or cycloalkylgroup containing up to 5 carbon atoms, preferably a methyl group,preferably in the presence of a base, for example an alkali metalhydride, such as sodium hydride, or an amine, preferably a tertiaryamine, such as triethylamine, in an inert solvent, for example toluene,dimethylformamide, or an ether, such as tetrahydrofuran or diethylether, at a temperature from about 0° C. to reflux, then a second base,for example an amine, such as piperidine.

Alternatively, compounds of formula I, wherein R¹, R², R³, Q¹, Q² and Q³are as hereinbefore defined, Z, Z¹ and Z² are oxygen, and Z³ representsa —CZNH— linkage, may be prepared by the reaction of compounds offormula V hereinafter depicted, wherein R¹ and R² are as hereinbeforedefined, Q¹, Q²

and Q³ are independently CH or N and at least one of Q¹, Q² and Q³ is N,with compounds of formula VI wherein R³ and X are as hereinbeforedefined,R³X  VIpreferably X is chloro, and preferably the preparation takes place inthe presence of a base, for example an alkali metal hydride, such assodium hydride, an alkali metal alkoxide, such as potassium t-butoxide,an alkali metal hydroxide, such as sodium hydroxide or carbonate, or anamine, preferably a tertiary amine, such as triethylamine or pyridine,optionally in an inert solvent, for example dichloromethane,dimethylformamide, or an ether, such as diethyl ether ortetrahydrofuran, preferably at a temperature from about 0° C. to reflux.

Alternatively, compounds of formula I, wherein R¹, R², R³, Z, Z¹, Q¹, Q²and Q³ are as hereinbefore defined, Z³ represents a —CZNH— linkage, andZ and Z² are oxygen, may be prepared by the reaction of compounds offormula VII wherein R¹, R³, Z, Z¹, Q¹, Q² and Q³ are as hereinbeforedefined and

Z³ represents a —CZNH— linkage, and Z is oxygen, with compounds of theformula VIII wherein R² is as hereinbefore defined, preferably, X is asR²X  VIIIhereinbefore defined or p-toluenesulfonate, preferably X is bromo, andpreferably the preparation takes place in the presence of a base, forexample an alkali metal hydride, such as sodium hydride, an alkali metalhydroxide or carbonate, such as sodium hydroxide or carbonate, or anamine, preferably a tertiary amine, such as. triethylamine or pyridine,optionally in an inert solvent, for example dichloromethane,dimethylformamide, or an ether, such as diethyl ether ortetrahydrofuran, preferably at a temperature from about 0° C. to reflux,or by the reaction of the compound of formula VII above with compoundsof the formula XXI, as hereinbelow defined in the presence of, forexample, diisopropylazodicarboxylate and triphenylphosphine.

Alternatively, compounds of formula I, wherein R¹, R², R³, Z¹, Z², Q¹,Q² and Q³ are as hereinbefore defined, Z³ represents a —CZCH₂— linkage,and Z represents oxygen, are prepared from compounds of formula IXwherein R¹,

R², R³, Z¹, Z², Q¹, Q² and Q³ are as hereinbefore defined, by oxidationby the application or adaptation of known methods. The oxidation iscarried out, for example, by reaction with oxalyl chloride and dimethylsulfoxide, in the presence of a base, preferably a tertiary amine,preferably triethylamine, in an inert solvent such as dichloromethane,at temperatures from about −60° C. to about room temperature, preferablyat a reduced temperature, or by adaptation of known methods for thepreparation of ketone from a secondary alcohol, for example theapplication of pyridinium dichromate. Alternatively, the oxidation iscarried out by reaction with chromium trioxide in the presence of3,5-dimethylpyrazole.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z, Z¹, Z², Q¹, Q² and Q³ are ashereinbefore defined, Z³ represents a —CZCH₂— linkage, and preferablythose wherein Z represents oxygen, are prepared from compounds offormula X wherein R¹,

R², Z, Z¹, Z², Q¹, Q² and Q³ are as hereinbefore defined and R⁵ and R⁶represent lower alkyl, such as methyl, groups, by coupling withcompounds of the formula XI wherein R³ is as hereinbefore defined, inthe presence of aR³CH₃  XIstrong base such as lithium diisopropylamide (usually prepared in situfrom n-butyl lithium and diisopropylamine), preferably at a lowtemperature.

Alternatively, compounds of formula I, wherein R¹, R², R³, Z¹, Z², Q¹,Q² and Q³ are as hereinbefore defined, Z³ represents a —CZCH₂— linkage,and Z represents oxygen, are prepared from compounds of formula XIIwherein R¹,

R², Z¹, Z², Q¹, Q² and Q³ are as hereinbefore defined, and R⁷ is alkyl,cycloalkyl or aralkyl containing up to 8 carbon atoms, by coupling withcompounds of the formula XI above, wherein R³ is as hereinbeforedefined, in the presence of a strong base, such as an alkali metal amideor alkyl, for example n-butyl lithium or lithium diisopropylamide(usually prepared in situ from butyl lithium and diisopropylamine), inan inert solvent, for example cyclohexane or an ether, such astetrahydrofuran or diethyl ether, at a temperature from about −78° C. toabout room temperature.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹, Z², Q¹, Q² and Q³ are as hereinbeforedefined and Z³ represents a —CH₂—NH— linkage are prepared by thereaction of compounds of formula XIII wherein R¹, R², Z¹, Z², Q¹, Q² andQ³ are as

hereinbefore defined, with compounds of formula III above, wherein R³ isas hereinbefore defined, followed by reduction with a compound such assodium cyanoborohydride. This process is especially suitable forcompounds wherein R³ represents an optionally substituted phenyl ornaphthyl group.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹, Z², Q¹, Q² and Q³ are as hereinbeforedefined and Z³ represents a —CH₂—NH— linkage are prepared by thereaction of compounds of formula XIV wherein X, R¹, R², Z¹, Z², Q¹, Q²and Q³ are as

herein before defined, and X is preferably bromo, with compounds offormula III above, wherein R³ is as hereinbefore defined, preferably inthe presence of a base such as sodium hydride. This process isespecially suitable for compounds wherein R³ represents an optionallysubstituted heteroaryl group.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹, Z², Q¹, Q² and Q³ are as hereinbeforedefined and Z³ represents a trans —CH═CH— linkage are prepared by thereaction of compounds of formula XIII above, wherein R¹, R², Z¹, Z², Q¹,Q² and Q³ are as hereinbefore defined, with the reaction product of acompound of the formula XV wherein R³ is as hereinbefore defined, R⁸represents(R⁸PCH₂R³)⁺(X)⁻  XVan aryl, such as phenyl group, and X represents halo, preferably bromo,with a base such as an alkali metal alkoxide, for example potassiumt-butoxide. The reaction is preferably carried out in a solvent such astetrahydrofuran.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹, Z², Q¹, Q² and Q³ are as hereinbeforedefined and Z³ represents a —CF₂—O— linkage are prepared by the reactionof compounds of formula XVI, wherein R¹, R², Z¹, Z², Q¹, Q² and Q³ arewherein

R¹, R², Z¹, Z², Q¹, Q² and Q³ are as hereinbefore defined, withcompounds of the formula XVII wherein R³ is as hereinbefore defined,preferably with the aidR³OH  XVIIof a base such as sodium hydride, preferably in a solvent such astetrahydrofuran.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹, Z², Q¹, Q² and Q³ are as hereinbeforedefined and Z³ represents a —CH₂—O— linkage are prepared by the reactionof compounds of formula XVIII wherein R¹, R², Z¹, Z², Q¹, Q² and Q³ areas

hereinbefore defined, with compounds of the formula VI hereinbefore,wherein R³ and X are as hereinbefore defined, preferably with the aid ofa base such as an alkali metal alkoxide, such as potassium t-butoxide.The reaction is preferably carried out in a solvent such astetrahydrofuran.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹, Z², Q¹, Q² and Q³ are as hereinbeforedefined and Z³ represents a —CH₂—O— linkage are prepared by the reactionof compounds of formula XIV above, wherein R¹, R², Z¹, Z², Q¹, Q², Q³and X are as hereinbefore defined, with compounds of formula XVII above,wherein R³ is as hereinbefore defined, preferably with the aid of a basesuch as an alkali metal alkoxide, such as potassium t-butoxide.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹, Z², Q¹, Q² and Q³ are as hereinbeforedefined and Z³ represents a —CO—CO— linkage are prepared by theoxidation of compounds of formula IX above, wherein R¹, R², R³, Z¹, Z²,Q¹, Q² and Q³ are as hereinbefore defined, for example by reaction withpyridinium dichromate, preferably in a solvent such as dichloromethane.This reaction is particularly suitable for compounds wherein R³represents a heteroaryl, preferably an optionally substituted pyridyl,group.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹, Z², Q¹, Q² and Q³ are as hereinbeforedefined and Z³ represents a —CH₂—S— linkage are prepared by the reactionof compounds of formula XIV above, wherein X, R¹, R², Z¹, Z², Q¹, Q² andQ³ are as hereinbefore defined, with compounds of the formula XX whereinR³ isR³—SH  XXas hereinbefore defined, preferably with the aid of a base such as analkali metal carbonate, such as potassium carbonate. Compounds offormula I wherein Z³ is —CH₂—S—, preferably wherein Z, Z¹ and Z² eachrepresent oxygen, and R² is alkyl or cycloalkyl, may then be oxidized tothe corresponding sulphinyl or sulphonyl group. For example, theoxidation to —CH₂—SO— can be carried out by means of potassium hydrogenperoxomonosulfate in a medium such as aqueous methanol. For example, theoxidation to —CH₂—SO₂— can be carried out by means of sodium iodate in amedium such as aqueous methanol.

According to another feature of the invention, compounds of formula Iwherein R¹, R², R³, Z¹, Z³, Q¹, Q² and Q³ are as hereinbefore defined,and R² represents cyclosulphonylalkyl, cyclosulphinylalkyl,cyclosulphonylalkenyl or cyclosulphinylalkenyl, are prepared byoxidizing the corresponding compounds of formula I wherein R² representscyclosulphonylalkyl or cyclosulphinylalkyl. For example, the oxidationto sulphinyl can be carried out by means of potassium hydrogenperoxomonosulfate in a medium such as aqueous methanol. For example, theoxidation to sulphonyl can be carried out by means of sodium iodate in amedium such as aqueous methanol.

As another example, compounds of formula I wherein R¹, R², R³, Z¹, Z²,Q¹, Q² and Q³ are as hereinbefore defined, and Z³ represents a cis —C═C—isomer linkage are prepared by the action of ultraviolet radiation uponthe trans-isomer.

As another example, compounds of formula I wherein R¹, R², R³, Z¹, Z¹,Q¹, Q² and Q³ are as hereinbefore defined, and Z³ contains a —CS—moiety, are prepared from compounds of formula I wherein R¹, R², R³, Z¹,Z², Q¹, Q² and Q³ are as hereinbefore defined, and Z³ contains a —CO—moiety, by reaction with phosphorus pentasulfide or2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide,preferably in a solvent such as pyridine or toluene, and preferably at atemperature from about 0° C. to reflux.

As another example, compounds of formula I wherein R³ is as hereinbeforedefined and contains an alkylsulfonyl, arylsulfonyl, alkylsulfinyl orarylsulfinyl group, R¹, R², Q¹, Q², Q³, Z, Z¹, Z² and Z³ are ashereinbefore defined, are prepared by oxidising the correspondingcompounds of formula I wherein R³ is as hereinbefore defined andcontains an alkylthio or arylthio group, R¹, R², Q¹, Q², Q³, Z, Z¹, Z²and Z³ are as hereinbefore defined, preferably wherein Z, Z¹ and Z² eachrepresent oxygen, and R² is alkyl or cycloalkyl, preferably with aperoxyacid, such as 3-chloroperbenzoic acid, preferably in an inertsolvent, such as dichloromethane, preferably at about room temperature.Alternatively, the oxidation is carried out by reaction with aperoxomonosulfate, such as potassium peroxomonosulfate, conveniently ina solvent such as methanol, buffered to about pH 5, at temperatures fromabout 0° C. to about room temperature. This latter method is preferredfor compounds containing an acid-labile group, such as those wherein themoiety R² is unsaturated, such as a cyclopent-2-enyloxy group.

As another example, compounds of formula I wherein R³ is as hereinbeforedefined and contains a hydroxymethyl group, and R¹, R², Q¹, Q², Q³, Z,Z¹, Z² and Z³ are as hereinbefore defined, are prepared by the reductionof the corresponding compounds of formula I wherein R³ is ashereinbefore defined and contains an aryloxycarbonyl or, preferably,alkoxycarbonyl group, R¹, R², Q¹, Q², Q³, Z, Z¹, Z² and Z³ are ashereinbefore defined, and Z is preferably oxygen, preferably by means ofreacting an alkali metal borohydride, preferably in an inert solvent,such as tetrahydrofuran, preferably at about room temperature.

As another example, compounds of formula I wherein R³ is as hereinbeforedefined and contains a formyl group, and R¹, R², Q¹, Q², Q³, Z, Z¹, Z²and Z³ are as hereinbefore defined, are prepared by the oxidising thecorresponding compounds of formula I wherein R³ is as hereinbeforedefined and contains a hydroxymethyl group, R¹, R², Q¹, Q², Q³, Z, Z¹,Z² and Z³ are as hereinbefore defined, and Z preferably being an oxygenatom, for example with oxalyl chloride and dimethyl sulfoxide, in asolvent such as dichloromethane, and preferably at a temperature lowerthan about −65° C., or, preferably, by reaction with a complex of sulfurtrioxide with an amine such as pyridine, preferably in the presence ofan amine such as triethylamine, preferably at about room temperature.

As another example, compounds of formula I wherein R³ is as hereinbeforedefined and contains an amino group, and R¹, R², Q¹, Q², Q³, Z, Z¹, Z²and Z³ are as hereinbefore defined, are prepared by the reducing thecorresponding compounds of formula I wherein R³ is as hereinbeforedefined and contains a nitro group, R¹, R², Q¹, Q², Q³, Z, Z¹, Z² and Z³are as hereinbefore defined, and Z is preferably oxygen, preferably withiron in acidic conditions, such as in acetic acid, preferably at orabove room temperature, more especially at the reflux temperature.Alternatively the reduction are carried out by reaction with hydrazinehydrate in the presence of ferric chloride and activated carbon,conveniently in a solvent such as methanol, at temperatures from about25° C. to about 80° C. This latter method is preferred for compoundscontaining an acid-labile group, such as those wherein the moiety R² isunsaturated, such as a cyclopent-2-enyloxy group.

As another example, compounds of formula I wherein R³ is as hereinbeforedefined and contains an alkanoylamino or aroylamino group, and R¹, R²,Q¹, Q², Q³, Z, Z¹, Z² and Z³ are as hereinbefore defined, are preparedfrom compounds of formula I wherein R³ is as hereinbefore defined andcontains an amino group, R¹, R², Q¹, Q², Q³, Z, Z¹, Z² and Z³ are ashereinbefore defined, and Z is preferably oxygen, preferably by means ofreaction with the appropriate acid halide or acid anhydride in thepresence of a tertiary base, such as triethylamine, optionally in aninert solvent, and preferably at a temperature from about 0° C. toreflux.

Compounds of formula I wherein R³ is as hereinbefore described,including an azaheteroaryl group containing one or more nitrogen ringatoms, preferably imine (═N—), and R¹, R², Q¹, Q², Q³, Z, Z¹, Z² and Z³are as hereinbefore defined, may be converted to the correspondingcompounds wherein a nitrogen atom of the azaheteroaryl moiety isoxidised to an N-oxide, R¹, R², Q¹, Q², Q³, Z, Z¹, Z² and Z³ arehereinbefore defined, and preferably Z, Z¹ and Z² each represent oxygen,and R² is alkyl or cycloalkyl, preferably by reacting a peracid, forexample peracetic acid in acetic acid or m-chloroperoxybenzoic acid inan inert solvent such as dichloromethane, at a temperature from aboutroom temperature to reflux, preferably at elevated temperature.Preferably wherein Z, Z¹ and Z² each represent oxygen, and R² is anoxidised cyclothioalkyl, such as cyclosulphinyl or sulphonyl, thereaction is carried out at a temperature from about room temperature toreflux, preferably at a reduced temperature. Alternatively, theoxidation is carried out by reaction with hydrogen peroxide in thepresence of sodium tungstate at temperatures from about room temperatureto about 60° C. This latter method is preferred for compounds containingan acid-labile group, such as those wherein the moiety R² contains acarbon-carbon double bond between its beta- and gamma-carbon atoms, suchas a cyclopent-2-enyloxy group.

Compounds of formula I wherein R³ represents an azaheteroaryl groupcontaining a nitrogen ring atom as an N-oxide, and R¹, R², Q¹, Q², Q³,Z, Z¹, Z² and Z³ are as hereinbefore defined, may be converted to thecorresponding compounds wherein Q¹, Q² or Q³ as a nitrogen atom isoxidised to an N-oxide moiety, R¹, R², Z, Z¹, Z² and Z³ are hereinbeforedefined, and preferably wherein Z, Z¹ and Z² each represent oxygen, andR² is alkyl or cycloalkyl, by reacting a peracid, for examplem-chloroperoxy-benzoic acid in an inert solvent such as dichloromethane,at a temperature from about room temperature to reflux, preferably atelevated temperature.

Compounds of formula I wherein R³ represents a azaheteroaryl groupcontaining one or more nitrogen ring atoms, preferably imine (═N—), andR¹, R², Q¹, Q², Q³, Z, Z¹, Z² and Z³ are as hereinbefore defined, may beconverted to the corresponding compounds wherein a nitrogen atom of theazaheteroaryl moiety is oxidised to an N-oxide, wherein Q¹, Q² or Q³ asa nitrogen atom is oxidised to an N-oxide moiety, R¹, R², Z, Z¹, Z² andZ³ are hereinbefore defined, and preferably wherein Z, Z¹ and Z² eachrepresent oxygen, and R² is alkyl or cycloalkyl, preferably by reactinga peracid, for example m-chloroperoxybenzoic acid in an inert solventsuch as dichloromethane, at a temperature from about room temperature toreflux, preferably at elevated temperature.

Compounds of formula I wherein R³ represents an azaheteroaryl groupcontaining a nitrogen ring atom as an N-oxide, Q¹, Q² or Q³ as anitrogen atom is oxidised to an N-oxide moiety, and R¹, R², Z, Z¹, Z²and Z³ are as hereinbefore defined, may be converted to thecorresponding compounds wherein R³ represents an azaheteroaryl groupcontaining one or more nitrogen ring atoms, preferably imine (═N—), Q¹,Q² or Q³ as a nitrogen atom is oxidised to an N-oxide moiety, R¹, R², Z,Z¹, Z² and Z³ are hereinbefore defined, preferably by reacting in adeoxygenating system, for example diphosphorus tetraiodide in an inertsolvent, such as dichloromethane, preferably at room temperature, orwith a chlorotrialkylsilane, preferably chlorotrimethylsilane, in thepresence of an alkali metal iodide, e.g potassium iodide, and zinc, inan inert solvent, for example acetonitrile, at temperatures from about0° C. to about room temperature, preferably at reduced temperature.

For example, compounds of formula I wherein R¹ is as hereinbeforedefined and is substituted by fluorine on a carbon atom thereof alpha tothe attachment of R¹ to Z¹ as sulfur, or wherein R² is as hereinbeforedefined and is substituted by fluorine on a carbon atom thereof alpha tothe attachment of R² to Z² as sulfur, and Q¹, Q², Q³, R³ and Z³ ashereinbefore defined, are prepared by reacting xenon difluoride withcorresponding compounds of formula I wherein said alpha-carbon atomscarry hydrogen atoms instead of said fluorine atoms. The reaction isconveniently carried out in a solvent, such as dichloromethane, in thepresence of a molecular sieve, and in an inert atmosphere, at a lowtemperature, such as at about 0° C. Alternatively, compounds of formulaI wherein R¹ is a difluoromethyl group may be prepared by reacting acompound of formula I or precursor wherein Z¹ is hydroxy or thiol withHCBrF₂ in the presence of a strong base in an inert solvent.

As another example, compounds of formula I wherein R³ represents aheteroaryl group containing one or more nitrogen ring atoms but carryingno halogen substituents, and R¹, R², R³, Z¹, Z², Z³, Q¹, Q² and Q³ areas hereinbefore defined, are prepared by the reduction of thecorresponding compounds of formula I wherein R³ does carry one or morehalo, such as chloro, substituents, for example by means of ammoniumformate in the presence of a palladium catalyst.

The compounds of the present invention are useful in the form of thefree base or acid or in the form of a pharmaceutically acceptable saltthereof. All forms are within the scope of the invention.

Where the compound of the present invention is substituted with a basicmoiety, acid addition salts are formed and are simply a more convenientform for use; and in practice, use of the salt form inherently amountsto use of the free base form. The acids which can be used to prepare theacid addition salts include preferably those which produce, whencombined with the free base, pharmaceutically acceptable salts, that is,salts whose anions are non-toxic to the patient in pharmaceutical dosesof the salts, so that the beneficial inhibitory effects on TNF and PDEinherent in the free base are not vitiated by side effects ascribable tothe anions. Although pharmaceutically acceptable salts of said basiccompounds are preferred, all acid addition salts are useful as sourcesof the free base form even if the particular salt, per se, is desiredonly as an intermediate product as, for example, when the salt is formedonly for purposes of purification, and identification, or when it isused as intermediate in preparing a pharmaceutically acceptable salt byion exchange procedures. Pharmaceutically acceptable salts within thescope of the invention are those derived from the following acids:mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acidand sulfamic acid; and organic acids such as acetic acid, citric acid,lactic acid, tartaric acid, malonic acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,cyclohexylsulfamic acid, quinic acid, and the like. The correspondingacid addition salts comprise the following: hydrohalides, such ashydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate,acetate, citrate, lactate, tartarate, malonate, oxalate, salicylate,propionate, succinate, fumarate, maleate,methylene-bis-beta-hydroxynaphthoates, gentisates, mesylates,isethionates and di-p-toluoyltartratesmethanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate,respectively.

According to a further feature of the invention, acid addition salts ofthe compounds of this invention are prepared by reaction of the freebase with the appropriate acid, by the application or adaptation ofknown methods. For example, the acid addition salts of the compounds ofthis invention are prepared either by dissolving the free base inaqueous or aqueous-alcohol solution or other suitable solventscontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and acid in an organicsolvent, in which case the salt separates directly or can be obtained byconcentration of the solution.

The acid addition salts of the compounds of this invention can beregenerated from the salts by the application or adaptation of knownmethods. For example, parent compounds of the invention can beregenerated from their acid addition salts by treatment with an alkali,such as aqueous sodium bicarbonate solution or aqueous ammonia solution.

Where the compound of the invention is substituted with an acidicmoiety, base addition salts may be formed and are simply a moreconvenient form for use; and in practice, use of the salt forminherently amounts to use of the free acid form. The bases which can beused to prepare the base addition salts include preferably those whichproduce, when combined with the free acid, pharmaceutically acceptablesalts, that is, salts whose cations are non-toxic to the animal organismin pharmaceutical doses of the salts, so that the beneficial inhibitoryeffects on TNF and PDE inherent in the free acid are not vitiated byside effects ascribable to the cations. Pharmaceutically acceptablesalts, including for example alkali and alkaline earth metal salts,within the scope of the invention are those derived from the followingbases: sodium hydride, sodium hydroxide, potassium hydroxide, calciumhydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide,zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylenediamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)-aminomethane,tetramethylammonium hydroxide, and the like.

Metal salts of compounds of the present invention may be obtained bycontacting a hydride, hydroxide, carbonate or similar reactive compoundof the chosen metal in an aqueous or organic solvent with the free acidform of the compound. The aqueous solvent employed may be water or itmay be a mixture of water with an organic solvent, preferably an alcoholsuch as methanol or ethanol, a ketone such as acetone, an aliphaticether such as tetrahydrofuran, or an ester such as ethyl acetate. Suchreactions are normally conducted at ambient temperature but they may, ifdesired, be conducted with heating.

Amine salts of compounds of the present invention may be obtained bycontacting an amine in an aqueous or organic solvent with the free acidform of the compound. Suitable aqueous solvents include water andmixtures of water with alcohols such as methanol or ethanol, ethers suchas tetrahydrofuran, nitriles such as acetonitrile, or ketones such asacetone. Amino acid salts may be similarly prepared.

The base addition salts of the compounds of this invention can beregenerated from the salts by the application or adaptation of knownmethods. For example, parent compounds of the invention can beregenerated from their base addition salts by treatment with an acid,such as hydrochloric acid.

As will be self-evident to those skilled in the art, some of thecompounds of this invention do not form stable salts. However, acidaddition salts are most likely to be formed by compounds of thisinvention wherein R³ represents a nitrogen-containing heteroaryl groupand/or wherein R³ contains an amino group as a substituent. Preferableacid addition salts of the compounds of the invention are those whereinR² is other than an acid labile group.

As well as being useful in themselves as active compounds, salts ofcompounds of the invention are useful for the purposes of purificationof the compounds, for example by exploitation of the solubilitydifferences between the salts and the parent compounds, side productsand/or starting materials by techniques well known to those skilled inthe art.

It will be apparent to those skilled in the art that certain compoundsof formula I can exhibit isomerism, for example geometrical isomerismand optical isomerism. Optical isomers include compounds of theinvention having asymmetric centers that may independently be in eitherthe R or S configuration. Geometrical isomers include the cis and transforms of compounds of the invention having alkenyl moieties. Individualgeometrical isomers, stereoisomers and mixtures thereof are within thescope of the present invention.

Such isomers can be separated from their mixtures, by the application oradaptation of known methods, for example chromatographic techniques andrecrystallization techniques, or they are separately prepared from theappropriate isomers of their intermediates, for example by theapplication or adaptation of methods described herein.

The starting materials and intermediates are prepared by the applicationor adaptation of known methods, for example methods as described in theReference Examples or their obvious chemical equivalents.

For example, compounds of formula II, wherein R¹, R², Q¹, Q², Q³, Z¹ andZ² are as hereinbefore defined, are prepared from compounds of formulaXIX wherein R¹, R², Q¹, Q², Q³, Z¹ and Z² are as hereinbefore defined,by the

application or adaptation of known methods for the preparation of acidhalides from carboxylic acids. For example, when the moiety X in acompound of formula II represents a chloro, the reaction may be carriedout by means of thionyl chloride or, preferably, oxalyl chloride in thepresence of triethylamine, or as prepared by adaptation of theprocedures described by K. R. Reistad et al., Acta. Chemica.Scandanavica B, 28, 667-72 (1974), incorporated herein by reference.

Compounds of formula XIX, wherein R¹, R², Q¹, Q², Q³, Z¹ and Z² are ashereinbefore defined, are prepared by the oxidation of compounds offormula XIII above, wherein R¹, R², Q¹, Q², Q³, Z¹ and Z² are ashereinbefore defined, for example by means of reaction with potassiumpermanganate, or with a mixture of sulfamic acid and sodium chlorite inacetic acid, or with sodium chlorite in the presence of sodiumdihydrogen phosphate.

According to a further feature of the invention, compounds of formulaXIX, wherein R¹, R², Q¹, Q², Q³, Z¹ and Z² are as hereinbefore defined,are prepared by the oxidation of compounds of formula XVIII,

by adaptation of known methods for the preparation of carboxylic acidsfrom primary alcohols, for example potassium permanganate in water or amixture of water and inert organic solvent, e.g dichloromethane, in thepresence of a phase transfer catalyst, such as aliquat 336, at aboutroom temperature to reflux. Alternatively, the compound of formula XVIIIis oxidized as described by H. C. Beyerman, Receueil, 77, 249-57,(1958), incorporated herein by reference.

Compounds of formula XIII, wherein R¹, R², Q¹, Q², Q³, Z¹ and Z² are ashereinbefore defined, are prepared from compounds of formula XX

wherein R¹, Q¹, Q², Q³ and Z¹ are as hereinbefore defined, by reactionwith compounds of formula VIII wherein R² and X are as hereinbeforedefined, and X is preferably bromo, preferably in the presence of abase, for example an alkali metal hydride, such as sodium hydride, analkali metal hydroxide or carbonate, such as sodium hydroxide orcarbonate, or an amine, preferably a tertiary amine, such astriethylamine or pyridine, optionally in an inert solvent, for exampledichloromethane, dimethylformamide, or an ether, such as diethyl etheror tetrahydrofuran, preferably at a temperature from about 0° C. toreflux, or alternatively by reaction with compounds of the formula XXI,wherein R² isR²OH  XXIas hereinbefore defined, preferably in the presence of a compound suchas diisopropyl azodicarboxylate and triphenylphosphine.

Alternatively compounds of formula XIX above, wherein R¹, R², Q¹, Q²,Q³, Z¹ and Z² are as hereinbefore defined, are prepared by thehydrolysis of compounds of formula XII above, wherein R¹, R², R⁷, Q¹,Q², Q³, Z¹ and Z² are as hereinbefore defined, for example by reactionwith a base, such as an aqueous alkali metal hydroxide, alkali metalcarbonate or bicarbonate, such as potassium hydroxide or potassiumcarbonate, in an inert co-solvent such as methanol at a temperature fromabout room temperature to reflux, and then with an aqueous acid such ashydrochloric acid or acetic acid.

Compounds of formula XIII above, wherein R¹, R², R⁷, Q¹, Q², Q³, Z¹ andZ² are as hereinbefore defined, are prepared from compounds of formulaXXII

by reaction with compounds of the formula XXI above, wherein R² is aswherein R¹, R⁷, Q¹, Q², Q³, Z¹ and Z² are as hereinbefore defined,preferably in the presence of diisopropyl azodicarboxylate andtriphenylphosphine.

Alternatively, compounds of formula XII above, as hereinbefore defined,can be prepared from compounds of formula XXII above, as hereinbeforedefined, by reaction with compounds of the formula VIII above, ashereinbefore defined, in the presence of base, for example an alkalimetal hydride, such as sodium hydride, a tertiary amine, such astriethylamine, or preferably an alkali metal carbonate or hydroxide,such as sodium carbonate or hydroxide, or in the presence of atransition metal carbonate, such as silver carbonate, optionally in aninert solvent, such as dimethylformamide or tetrahydrofuran, preferablyat a temperature from about 0° C. to about 80° C.

Compounds of formula IX above, wherein R¹, R², R³, Q¹, Q², Q³, Z¹ Z² andZ³ are as hereinbefore defined, are prepared by the reaction ofcompounds of formula XIII above, wherein R¹, R², Q¹, Q², Q³, Z¹ and Z¹are as hereinbefore defined, with compounds of the formula XI above,wherein R³ is as hereinbefore defined, in the presence of a base such asan alkali metal amide or alkyl, for example butyllithium or lithiumdiisopropylamide, in an inert solvent, for example cyclohexane or anether, such as tetrahydrofuran or diethyl ether, at a temperature fromabout −78° C. to about room temperature, preferably at a reducedtemperature.

Compounds of formula XVI above, wherein R¹, R², Q¹, Q², Q³, Z¹ and Z²are as hereinbefore defined, are prepared by the reaction of bromine incarbon tetrachloride and ultraviolet radiation on the correspondingcompounds wherein the bromodifluormethyl moiety is —CHF₂, whichthemselves are prepared by the action of sulfur tetrafluoride andhydrofluoric acid on compounds of formula XIII above, wherein R¹, R²,Q¹, Q², Q³, Z¹ and Z² are as hereinbefore defined, in the presence ofpyridine.

Compounds of formula XIII above, wherein R¹, R², Q¹, Q², Q³, Z¹ and Z²are as hereinbefore defined, are prepared from compounds of formulaXVIII above, R¹, R², Q¹, Q², Q³, Z¹ and Z² are as hereinbefore defined,by a Swern oxidation using a mixture of dimethyl sulphoxide and oxalylchloride in the presence of a base, preferably a tertiary amine,preferably triethylamine, in an inert solvent e.g dichloromethane, attemperatures from about −60° C. to about room temperature, or preferablyusing activated manganese dioxide in an inert solvent, for exampledichloromethane or diethyl ether, preferably at about room temperature.

Compounds of formula XXII above, wherein R¹, R⁷, Q¹, Q², Q³ and Z¹ areas hereinbefore defined, and Z² represents an oxygen atom are preparedfrom compounds of formula XXIII, wherein R¹, R⁷, Q¹, Q², Q³ and Z¹

as hereinbefore described, by diazotisation of the amino group with analkali metal nitrite, such as sodium nitrite, under aqueous acidconditions, such as aqueous hydrochloric acid, at room temperature orbelow, preferably at about 0° C. The diazo species is isolated by theaddition of an alkali metal salt which stabilises the diazonium salt,such as sodium tetrafluoroborate, at room temperature or below,preferably at about 0° C. The resulting stabilised diazonium salt isthen decomposed under acid conditions, such as trifluoroacetic acid, atelevated temperature, such as boiling point of the acid.

Alternatively, compounds of formula XXII above, wherein R¹, R⁷, Q¹, Q²,Q³ and Z¹ are as hereinbefore defined, and Z² represents a sulphur atomare prepared from compounds of formula XXIII above, wherein R¹, R⁷, Q¹,Q², Q³ and Z¹ are as hereinbefore defined, by diazotisation of the aminogroup with an alkali metal nitrite, such as sodium nitrite, underaqueous acid conditions, such as aqueous hydrochloric acid, at roomtemperature or below, preferably at about 0° C. The diazo species isisolated by the addition of an alkali metal salt which stabilises thediazonium salt, such as sodium tetrafluoroborate, at room temperature orbelow, preferably at about 0° C. The resulting stabilised diazonium saltis then reacted with a sulphydryl anion, such as sodium hydrogensulphide.

Compounds of formula XXIII above, wherein R¹, R⁷, Q¹, Q², Q³ and Z¹ areas hereinbefore defined, are prepared from compounds of formula XXIV

wherein R¹, R⁷, Q¹, Q², Q³ and Z¹ are as hereinbefore defined, byreduction of the nitro group with hydrogen and a metal catalyst, such as5% palladium supported on carbon, in an inert solvent, such as ethylacetate, or using a dissolving metal reduction, for example tin or zinc,preferably iron, in aqueous acid, for example hydrochloric acid, orpreferably acetic acid, optionally with an inert co-solvent, for exampleethanol, at a temperature from about room temperature to reflux,preferably at elevated temperature.

Compounds of formula XXIV above, wherein R¹, R⁷, Q¹, Q², Q³ and Z¹ areas hereinbefore defined, are prepared from compounds of formula XXV

wherein R⁷, Q¹, Q² and Q³ are as hereinbefore defined (prepared by themethod of Berrie et al. J. Chem. Soc. 2590-4 (1951), Ger. Offen.2,130,311 and U.S. Pat. No. 3,903,146, incorporated herein byreference), by reaction with compounds of formula XXVI, wherein Z¹ andR¹ are as hereinbefore defined,R¹Z¹M  XXVIand M represents an alkaline metal, such as sodium, in an alcohol, suchas methanol where Z¹ is oxygen, or inert solvent, for example where Z¹is sulphur, at room temperature or up to 80° C., preferably at roomtemperature.

Alternatively, compounds of formula XII above, wherein Z¹, R¹, and R⁷are as hereinbefore defined, and Q¹ and Q² are CH, and Q³ is nitrogenare prepared by reaction of compounds of formula XXVII, wherein X, Z¹,R¹ and R⁷

are as hereinbefore defined, with compounds of formula XXVI above,wherein Z², R² and M are as hereinbefore defined, preferably in thepresence of a base, for example alkali metal or alkali metal hydride,such as sodium or sodium hydride, without co-solvent or in the presenceof an inert solvent, such as tetrahydrofuran, from about roomtemperature to reflux, preferably at about room temperature.

Compounds of formula XXVII above, wherein Z¹, R¹ and R⁷ are as definedhereinbefore, are prepared by the reaction of compounds of formulaXXVIII, wherein X, Z¹ and R¹ are as hereinbefore defined, with compounds

of formula XXIX, wherein R⁷ is as hereinbefore defined, preferably usingtheR⁷OH  XXIXcompound of XXIX as the solvent, from about room temperature to reflux.

Compounds of formula XXVIII above, wherein X, R¹ and Z¹ are ashereinbefore defined, are prepared from compounds of formula XXX,wherein

X, R¹ and Z¹ are as hereinbefore defined, a by adaptation of proceduresdescribed by K. R. Reistad et al., Acta. Chemica. Scandanavica B, 28,667-72 (1974), incorporated herein by reference.

Compounds of formula XXX above, wherein X, R¹ and Z¹ are as hereinbeforedefined, are prepared by the reaction of compounds of formula XXXI,wherein X and Z¹ is as hereinbefore defined, with compounds of

formula XXXII, wherein R¹ is as hereinbefore defined, by adaptation of(R¹)₂SO₄  XXXIIprocedures described by K. R. Reistad et al., Acta. Chemica.Scandanavica B, 28, 667-72 (1974), incorporated herein by reference.

Alternatively, compounds of formula XVIII above, wherein Z¹ representsoxygen, Z² represent oxygen or sulphur atoms, Q¹ and Q³ represent CH,and Q² represents a nitrogen atom, and R¹ and R² are as hereinbeforedefined are prepared from compounds of formula XXXIII, wherein R¹, R²and Z² are as

hereinbefore defined, and P represents a protecting group, such as asilyl group, for example t-butyldimethylsilyl, or a trityl group, byreaction with an excess or a catalytic quantity of aqueous acid, forexample formic acid, trifluoroacetic acid or acetic acid, neat or in thepresence of a co-solvent, for example ethyl acetate, at a temperaturefrom about room temperature to about 100° C.

Compounds of formula XXXIII above, R¹, R², Z² and P are as hereinbeforedefined, are prepared by the reaction of compounds of formula XXXIV,wherein Y represents P¹ or R¹, P¹ represents a protecting group, such

as benzyl, and R¹, Z² and P are as hereinbefore defined, (1) where Y andZ² of XXXIV represent respectively R¹ and an oxygen atom, with compoundsof formula XXI, wherein R² is as hereinbefore defined, in the presenceof a dialkyl diazodiarboxylate, for examplediisopropyldiazodicarboxylate, and a phosphine, preferablytriarylphosphine, such as triphenylphosphine, in an inert solvent, forexample toluene or an ether, such as tetrahydrofuran or diethyl ether,at a temperature from about −20° C. to reflux, or (2) where Y and Z² ofXXXIV represent respectively R¹ and a sulphur atom, with compounds offormula VIII above, wherein R² and X are as hereinbefore defined, and Xis preferably bromo, preferably in the presence of a base, for examplean alkali metal hydride, such as sodium hydride, an alkali metalhydroxide or carbonate, such as sodium hydroxide or carbonate, or anamine, preferably a tertiary amine, such as triethylamine or pyridine,optionally in an inert solvent, for example dichloromethane,dimethylformamide, or an ether, such as diethyl ether ortetrahydrofuran, preferably at a temperature from about 0° C. to reflux,or (3) where Y of XXXIV represents P¹, a protecting group ashereinbefore defined, and Z² of XXXIV represents an oxygen or sulphuratom, then XXXIV is treated as in procedure (1) or (2) herein to preparecompounds of formula XXXV, wherein Y is P¹, and P, P¹, Z² and R² are asherein before defined,

that are then selectively deprotected to remove P¹ as a benzyl group,for example by hydrogenolysis in the presence of a supported metalcatalyst, such as 5% palladium on charcoal, in an inert solvent, forexample ethyl acetate, or preferably ethanol to yield compounds offormula XXXVI, wherein P, Z² and R²

are as hereinbefore defined, that are, then alkylated with compounds offormula XXXVII, wherein R¹ and X are hereinbefore defined, in thepresence of a base,R¹X  XXXVIIfor example an amine, such as 1,8-diazabicyclo[5.4.0]undec-7-ene, orpreferably an alkali metal carbonate, such as potassium carbonate, in aninert solvent, for example dimethylformamide, at a temperature fromabout 0° C. to about 120° C.

Compounds of formula XXXIV above, wherein Y, Z² and P are ashereinbefore defined, are prepared by the reaction of compounds offormula XXXVIII, wherein Y is as hereinbefore defined, and Z² representsan oxygen

atom, with compounds of formula XXXIX, wherein P and X are asPX  XXXIXhereinbefore defined, preferably in the presence of base, for example anamine, preferably a tertiary amine, for example triethylamine orpreferably 4-dimethylaminopyridine, in an inert solvent, for exampledimethylformamide or tetrahydrofuran, at from about room temperature toabout 120° C., preferably from about 60° C. to about 100° C., and theprotected product is optionally converted to the corresponding protectedproduct wherein Z² is sulphur, with phosphorus pentasulfide or2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide,preferably in a solvent such as pyridine or toluene, and preferably at atemperature from about 0° C. to reflux.

Compounds of formula XXXVIII above, wherein Z² represents an oxygenatom, and Y is as hereinbefore defined, are prepared from compounds offormula XXXX, wherein Y is as hereinbefore defined, by adaptation of the

procedures described by H. C. Beyerman, Receueil, 77, 249-57, (1958) andEuropean Patent 204207 (20/05/86), incorporated herein by reference.

Compounds of formula XXXX wherein Y is as hereinbefore defined, areprepared by the reaction of compounds of formula XXXXI, with compounds

of formula XXXII above, wherein R¹ is as hereinbefore defined, byadaptation of the alkylation procedure described by H. C. Beyerman,Receueil, 77, 249-57, (1958) and European Patent 204207 (20/05/86),incorporated herein by reference.

Compounds of formula XII above, wherein Z¹ and Z² represent an oxygenatoms, Q¹ and Q³ represent CH, Q² represents N, and R¹, R² and R⁷ are ashereinbefore defined are prepared by the reaction of compounds offormula XXXXII, wherein Z² represents an oxygen atom, and R¹ and R⁷ areas

hereinbefore defined, with compounds of formula XXI above, wherein R² isas hereinbefore defined, in the presence of a dialkyl diazodiarboxylate,for example diisopropyldiazodicarboxylate, and a phosphine, preferablytriarylphosphine, such as triphenylphosphine, in an inert solvent, forexample toluene or an ether, such as tetrahydrofuran or diethyl ether,at a temperature from about −20° C. to reflux.

Compounds of formula XXXXII above, wherein Z² represents an oxygen atom,and R¹ and R⁷ are as hereinbefore defined, are prepared by the reactionof compounds of formula XXXXIII, wherein R¹ and Z² are as

hereinbefore defined, with compounds of formula XXIX, wherein R⁷ is ashereinbefore defined, in the presence of an acid, preferably a mineralacid, for example sulphuric acid, or preferably hydrogen chloride, at atemperature from about 0° C. to reflux, preferably at an elevatedtemperature.

Compounds of formula XXXXIII above, wherein R¹ and Z² are ashereinbefore defined, are prepared from compounds of formula XXXVIIIabove, wherein Y is R¹, Z² represents an oxygen atom, and R¹ is ashereinbefore defined, by adaptation of the procedure described by H. C.Beyerman, Receueil, 77, 249-57, (1958), incorporated herein byreference.

Alternatively, compounds of formula XVIII above, wherein Q¹ and Q² areN, Q³ is CH, R¹ R² are as hereinbefore defined, and Z¹ and Z² representoxygen atoms, are prepared from compounds of formula XXXXIV, wherein R¹,

R², and R⁴ are as hereinbefore defined, by reaction with aqueous alkalimetal hydroxide or carbonate, such as potassium hydroxide or preferablypotassium carbonate, in an inert co-solvent, such as methanol, at atemperature from about room temperature to reflux.

Compounds of formula XXXXIV above, wherein R¹, R², and R⁴ are ashereinbefore defined, are prepared from compounds of formula XXXXV,

wherein R¹ and R² are as hereinbefore defined (prepared by adaptation ofthe method of M. Ogata and H. Kano, J. Heterocyclic Chem., 11, 29-35,(1963), incorporated herein by reference), by reaction with compounds ofthe formula XXXXVI, wherein R⁴ is as hereinbefore defined, preferably a(R⁴CO)₂O  XXXXVImethyl group, using compound XXXXVI as solvent at about room temperatureto reflux, preferably at elevated temperature.

The present invention is further exemplified but not limited by thefollowing illustrative examples which illustrate the preparation of thecompounds according to the invention. The Reference Examples illustratethe preparation of the intermediates.

In the nuclear magnetic resonance spectra (NMR) the chemical shifts areexpressed in ppm relative to tetramethylsilane. Abbreviations have thefollowing significance: s=singlet; d=doublet; t=triplet; m=multiplet;dd=doublet of doublets; ddd=doublet of doublets of doublets; dt=doubletof triplets, b=broad.

EXAMPLE 1 Compounds A-BH

A suspension of 3-cyclopentyloxy-6-fluoro-4-methoxybenzoic acid (0.88 g)in dry toluene (10 mL) is treated with thionyl chloride (2 mL) and themixture is refluxed for 90 minutes. The mixture is cooled andconcentrated in vacuo, to give “yellow oil A”.

A suspension of sodium hydride (0.4 g of a 60% dispersion in mineraloil) in dimethylformamide (5 mL) is treated with a solution of4-amino-3,5-dichloropyridine (0.82 g) in dimethylformamide (5 mL) andthe reaction mixture is stirred at room temperature for 30 minutes. Itis then treated with a solution of the “yellow oil A” indimethylformamide (5 mL) and stirred at 45° C. for 16 hours. It is thencooled, poured into water (50 mL) and extracted with chloroform (3×500mL). The combined extracts are dried over magnesium sulphate andconcentrated. The residual yellow oil is subjected to flashchromatography [a 3:1 mixture of petroleum ether (b.p. 60-80° C.) andethyl acetate is used as eluent in a silica gel column] to giveN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide(0.77 g), in the form of a white solid, m.p. 143-144° C. [Elementalanalysis:—C,53.75; H,4.28;N,7.29%. calculated:—C,54.15;H,4.29;N,7.02%.NMR (CDCl₃): 8.56(s, 1H), 8.37(d,1H,J=18 Hz),7.62 (d,1H,J=8 Hz),6.71(d,1H,J=14 Hz), 4.87-4.82(m,1H),3.93 (s,3H),2.03-1.57(m,8H)].

By proceeding in a similar manner, but replacing4-amino-3,5-dichloropyridine by the appropriate quantities of thecorresponding aniline or aminopyridine derivatives and acid chloridesthere are prepared:

-   N-(2,6-difluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2-chloro-6-fluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2-trifluoromethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,4,6-trichlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,6-dibromophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2-chloro-6-methylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,6-dichlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2-fluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-phenyl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2-methoxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(3-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(4-methoxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,6-dimethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2-methylthiophenyl)-3-cycloperityloxy-6-fluoro-4-methoxybenzamide;-   N-(2-bromophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2-methoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2-aminosulfonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2-benzoylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2-cyanophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,5-dichlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(3-methylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2-dimethylaminophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2-acetylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2-hydroxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-pyrid-2-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-pyrazin-2-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-pyrimidin-2-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(3-methylpyrid-2-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-pyrid-3-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(3-chloropyrid-2-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(3-chloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-pyrid-4-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(3,5-dimethylisoxazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(3,5-dibromopyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(3,5-dimethylpyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,6-dichloro-4-cyanophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,6-dichloro-4-methoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,3,5-trifluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(3,5-difluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(3-bromo-5-chloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,4,6-trifluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,6-dichloro-4-methoxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(4,6-dichloropyrimid-5-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,3,5,6-tetrafluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(3,5-dichloro-2,6-difluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(5-cyano-3-methylisothiazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,6-dichloro-4-carbamoylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(3-chloro-2,5,6-trifluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(4-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(3-methyl-5-bromoisothiazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(3,5-dimethylisothiazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,6-difluorophenyl)-3-cyclohexyloxy-6-fluoro-4-methoxybenzamide;-   N-(2,6-difluorophenyl)-3-butoxy-6-fluoro-4-methoxybenzamide; and-   N-(2,6-difluorophenyl)-3-propoxy-6-fluoro-4-methoxybenzamide.

EXAMPLE 2 Compounds BI-BJ

A solution of 4-amino-3,5-dichloropyridine (3.73 g) in drytetrahydrofuran (50 mL) under nitrogen at 5-10° C. is treatedportionwise with sodium hydride (60% dispersion in oil; 1.87 g). After30 minutes it is treated dropwise with a solution of3-cyclopent-2-enyloxy-4-methoxybenzoyl chloride in dry tetrahydrofuran(50 mL; that is prepared, as described in Reference Example 6, from 5.89g 3-cyclopent-2-enyloxy-4-methoxybenzoic acid). The resulting mixture isallowed to warm to room temperature and left to stand overnight. Most ofthe solvent is then removed under reduced pressure and the residue ispartitioned between water (250 mL) and dichloromethane (250 mL) and theaqueous layer is further extracted with dichloromethane (2×250 mL). Thecombined organic layers are dried over sodium sulfate, the solvent isremoved under reduced pressure, and the resulting residue is subjectedto flash chromatography on silica gel, eluting with mixtures of ethylacetate and pentane (3:7 to 1:1 v/v), to give a cream solid (1.25 g),which is recrystallized from a mixture of ethyl acetate and pentane, togive(±)-N-(3,5-dichloropyrid-4-yl)-3-cyclopent-2-enyloxy-4-methoxybenzamide(0.80 g), as a white solid, m.p. 177-178° C. [Elemental analysis: C,56.9; H, 4.2; N, 7.4; Cl, 18.6%. calculated: C, 57.0; H, 4.3; N, 7.4; Cl18.7%].

By proceeding in a similar manner, but using3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzoyl chloride (that isprepared, as described in Reference Example 6) there is preparedN-(3,5-dichloropyrid-4-yl)-3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzamide.

EXAMPLE 3 Compounds BK-BL

A solution of 4-amino-3,5-dichloropyridine (0.93 g) in drytetrahydrofuran (56 mL) under nitrogen at 5-10° C. is treatedportionwise with sodium hydride (60% dispersion in oil, 0.57 g). After 1hour it is treated dropwise with a solution of3-cyclopent-3-enyloxy-4-methoxybenzoyl chloride in dry tetrahydrofuran(30 mL) that is prepared as described in Reference Example 7 from 1.33 g3-cyclopent-3-enyloxy-4-methoxybenzoic acid. The resulting mixture isallowed to warm to room temperature, stirred for a further 3 hours andthen poured into 5% aqueous potassium carbonate (430 mL). The resultingemulsion is extracted with ethyl acetate (3×150 mL), the combinedorganic extracts washed with water (2×20 mL), followed by ice-cold 1 Maqueous hydrochloric acid (2×20 mL) and dried over sodium sulfate. Thesolvent is removed under reduced pressure and the resulting residuesubject to flash chromatography on silica gel, eluting with mixtures oft-butyl methyl ether and cyclohexane (2:3 to 7:3 v/v), to give a creamsolid, which is recrystallized from acetonitrile to giveN-(3,5-dichloropyrid-4-yl)-3-cyclopent-3-enyloxy-4-methoxybenzamide(0.54 g), as a white solid, m.p. 193-195° C. [Elemental analysis: C,56.7; H, 4.2; N, 7.3%. calculated: C, 57.0; H, 4.3; N, 7.4%].

By proceeding in a similar manner, but using3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzoyl chloride (that isprepared, as described in Reference Example 7) there is preparedN-(3,5-dichloropyrid-4-yl)-3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzamide.

EXAMPLE 4 Compounds BM-BN

A stirred solution ofN-(2-methylthiophenyl)-3-cyclopentyloxy-4-methoxybenzamide (1.80 g; thatis prepared as described hereinbefore in Example 5) is treated with asolution of 3-chloroperbenzoic acid (3.60 g; 85% pure) indichloromethane (72 mL), dropwise, and then it is stirred at roomtemperature for 5 hours. The reaction mixture is washed with saturatedaqueous sodium bicarbonate solution and then with water, and then it isdried over magnesium sulfate. The mixture is concentrated to giveN-(2-methylsulfonylphenyl)-3-cyclopentyloxy-4-methoxybenzamide, (1.12g), in the form of a white solid, m.p. 119-121° C. [NMR (CDCl₃):1.52-2.16 (m, 8H), 3.1 (s, 3H), 3.94 (s, 3H), 4.9 (m, 1H), 6.96 (d, 1H),7.46 (m, 1H), 7.6 (m, 2H), 7.7 (t, 1H), 7.95 (d, 1H), 8.68 (d, 1H);Elemental analysis: C, 61.6; H, 6.0; N, 3.5; S, 8.5%. Calculated: C,61.7; H, 5.95; N, 3.6; S, 8.5%].

By proceeding in a similar manner, but replacingN-(2-methylthiophenyl)-3-cyclopentyloxy-4-methoxybenzamide byN-(2-methylthiophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide,that is prepared as described above in Example 1), there is preparedN-(2-methylsulfonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide.

EXAMPLE 5 Compounds BO-BP

3-Cyclopentyloxy-4-methoxybenzoyl chloride (13.3 g) and 2-chloroaniline(6.6 g) are dissolved in pyridine (50 mL) and the solution is allowed tostand at room temperature for 1 hour. Phosphorus pentasulfide (13 g) isadded and the stirred mixture is heated at 110° C. for 1.5 hours. Aftercooling to room temperature the mixture is poured into an ice-coldsolution of concentrated hydrochloric acid (100 mL) in water (400 mL).The mixture is stirred for 1 hour and the yellow solid is collected,washed with water and subjected to flash chromatography on silica gel,eluting with a mixture of cyclohexane and ethyl:acetate (3:1 v/v), togive N-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxy(thiobenzamide) (5.4g), m.p. 129-131° C. [Elemental analysis: C, 62.6; H, 5.5; N, 3.9; S,8.9%. Calculated: C, 63.1; H, 5.6; N, 3.9; S, 8.9%].

By proceeding in a manner similar, but using3-cyclopentyloxy-6-fluoro-4-methoxybenzoyl chloride, instead of3-cyclopentyloxy-4-methoxybenzoyl chloride, there is preparedN-(2-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxy(thiobenzamide).

EXAMPLE 6 Compounds BQ-BR

A stirred solution ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (2.0 g)in toluene (50 mL) is treated with2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (3.0g), and the mixture is heated at 100° C. for 2 hours. After cooling toroom temperature and filtration, the filtrate is concentrated in vacuo,to give a yellow oil. This oil is subjected to flash chromatography onsilica gel, using a mixture of pentane and ethyl acetate (8:2 v/v) aseluent, to giveN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxy(thiobenzamide)(0.64 g) m.p. 118-119° C. [Elemental analysis: C, 54.1; H, 4.6; Cl,17.4; N, 6.8%. calculated: C, 54.4; H, 4.6; Cl, 17.85; N, 7.05%].

By proceeding in a manner similar, but replacing theN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide by theappropriate quantity ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide,which is prepared as described hereinafter in Example 1, there ispreparedN-(3,5-dichloropyrid-4yl)-3-cyclopentyloxy-6-fluoro-4-methoxy(thiobenzamide).

EXAMPLE 75 Compounds BS-BT

A solution ofN-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide (1.5g) in glacial acetic acid (22 mL) is treated with iron pin dust (1.3 g)and the mixture is heated with stirring at 90° C. for 1 hour. Thereaction mixture is cooled, basified to pH 8 by treatment with saturatedaqueous sodium carbonate solution, and extracted with ethyl acetate(2×150 mL). The combined organic extract is dried over magnesium sulfateand concentrated in vacuo, to give a white solid. This solid issubjected to flash chromatography, eluting with a mixture of ethylacetate and pentane (1:1 v/v), to giveN-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-4-methoxybenzamide (0.8g), m.p. 170-172° C. [Elemental analysis: C, 54.8; H, 5.04; N, 6.5; Cl,17.4%. calculated: C, 57.7; H, 5.1; N, 7.1; Cl, 17.9%].

By proceeding in a manner similar, but replacing theN-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide bythe appropriate quantity ofN-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide,which is prepared as described hereinafter in Example 1, there ispreparedN-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide.

EXAMPLE 8 Compounds BU-BV

Acetic anhydride (10 mL) is treated withN-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-4-methoxybenzamide (0.8g), and the reaction mixture is stirred for 2 hours and left to standovernight. It is then poured into water (100 mL), and extracted withethyl acetate (100 mL) and then with dichloromethane (100 mL). Theorganic extracts are combined, dried over magnesium sulfate, andevaporated, to giveN-(4-acetylamino-2,6-dichlorophenyl)-3-cyclopentyloxy-4-methoxybenzamide(0.4 g), m.p. 250-252° C. [Elemental analysis: C, 57.6; H, 5.05; N, 6.3;Cl, 16.1%. calculated: C, 57.5; H, 5.1; N, 6.4; Cl, 16.2%].

By proceeding in a manner similar, but replacing theN-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-4-methoxybenzamide bythe appropriate quantity ofN-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide,which is prepared as described hereinafter in Example 1, there ispreparedN-(2,6-dichloro-4-acetylaminophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide.

EXAMPLE 9 Compounds BW-BX

A stirred solution ofN-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyloxy-4-methoxybenzamide(6.1 g) in dry tetrahydrofuran (80 mL) at room temperature under argonis treated dropwise with a solution of lithium borohydride intetrahydrofuran (115 mL; 2 M). The mixture is stirred overnight and thenit is treated portionwise with saturated brine (200 mL) and stirred for30 minutes. The organic layer is then washed with water, dried overmagnesium sulfate and evaporated. The resulting residue is subjected toflash chromatography on silica gel, to giveN-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-4-methoxybenzamide(4.4 g), m.p. 174-176° C. [Elemental analysis: C, 57.1; H, 5.4; N, 2.9%.calculated C₂₀H₂₁O₄NCl₂:0.5H₂O: C, 57.3; H, 5.3; N, 3.3%].

By proceeding in a similar manner, but using the appropriate quantity ofN-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide(that is prepared as described in Example 1) instead ofN-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyloxy-4-methoxybenzamide,there is preparedN-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide.

EXAMPLE 10 Compounds BY-BZ

A solution ofN-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-4-methoxybenzamide(4.4 g; that is prepared as described in Example 9) in dichloromethane(30 mL) is treated with activated manganese dioxide (6.2 g), and themixture is stirred at reflux for 24 hours. The mixture is filtered, thefiltrate is evaporated, and the resulting residue is subjected to flashchromatography on silica gel, eluting with ethyl acetate, to giveN-(2,6-dichloro-4-formylphenyl)-3-cyclopentyloxy-4-methoxy-benzamide(2.4 g), m.p. 96-98° C. [Elemental analysis: C, 59.0; H, 5.1; N, 3.1%.calculated: C, 58.8; H, 4.7; N, 3.4%].

By proceeding in a similar manner, but using the appropriate quantity ofN-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide(that is prepared as described in Example 9) instead ofN-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-4-methoxybenzamide,there is preparedN-(2,6-dichloro-4-formylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide.

EXAMPLE 11 Compounds CA-CB

A solution ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (3.8 g)in dry tetrahydrofuran (25 mL) is treated with a suspension of sodiumhydride (60% dispersion in oil; 0.40 g), and the mixture is stirreduntil effervescence has ceased and a solution has formed. This solutionis evaporated in vacuo and the resulting residue is triturated witht-butyl methyl ether (20 mL). The resulting off-white solid is filteredoff, quickly washed with t-butyl methyl ether (2×20 mL) and dried, togive the sodium salt ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (3.5 g),m.p. 265-270° C. (with decomposition) [NMR (DMSO-D₆): 1.52-1.93 (m, 8H),4.77 (s, 3H), 4.75-4.80 (m, 1H), 6.98 (d, 1H), 7.58 (dd, 1H), 7.60 (s,1H), 8.20 (s, 2H); IR spectrum: strong peak at 1508 cm⁻¹, with no peaksat or near 1661 cm⁻¹ or 3244 cm⁻¹, which would have been characteristicsof the starting material].

By proceeding in a similar manner, but using the appropriate quantity ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide(that is described as in Example 1) instead ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide, there isprepared sodium salt ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide.

EXAMPLE 12 Compounds CC-CG

By proceeding in a similar manner as in Example 1, but using theappropriate quantities of the appropriate benzoic acid instead of3-cyclopentyloxy-6-fluoro-4-methoxybenzoic acid are prepared:—

(±)N-(3,5-dichloropyrd-4-yl)-3-exonorbornyloxy-6-fluoro-4-methoxybenzamide,m.p. 139-140° C. [Elemental analysis:—C, 56.6; H, 4.5; N, 6.6; Cl,16.6%. calculated:—C, 56.5; H, 4.5; N, 6.6; Cl, 16.7%].

N-(3,5-dichloropyrid-4-yl)-2-fluoro-5-isopropyloxy-4-methoxybenzamide,m.p. 154.5-156° C. [Elemental analysis:—C, 51.8; H, 4.2; N, 7.4; Cl,18.7%. calculated:—C, 51.5; H, 4.05; N, 7.5; Cl, 19.0%].

(±)N-(3,5-dichloropyrid-4-yl)-2-fluoro-4-methoxy-5-(tricyclo[2.2.1.0]hept-2-yloxy)benzamidehemihydrate, m.p. 149-151° C. [Elemental analysis:—C, 55.7; H, 4.0; N,6.2%. calculated:—C, 55.6; H, 4.2; N, 6.5%].

N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-difluoromethoxy-6-fluorobenzamide,m.p. 96-99° C. [Elemental analysis:—C, 50.1; H, 3.8; N, 6.6; Cl, 16.6%.calculated:—C, 49.7; H, 3.5; N, 6.4; Cl, 16.3%].

N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-2-fluoro-5-isopropyloxybenzamide,m.p. 105-108° C. [Elemental analysis:—C, 47.0; H, 3.2; N, 6.8; Cl,17.4%. calculated:—C, 47.0; H, 3.2; N, 6.85; Cl, 17.3%].

EXAMPLE 13 Compound CH

A solution of oxalyl chloride (0.05 mL) in dichloromethane (3 mL) iscooled to −60° C. and dimethylsulfoxide (1 mL) added. After stirring atthis temperature for 0.25 hours, a solution of2-(3,5-dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanol(0.2 g) in dichloromethane (5 mL) is added dropwise. After stirring at−60° C. for 0.25 hours, triethylamine (0.33 mL) is added dropwise andthe solution stirred for 0.25 hour at −60° C. and then at roomtemperature overnight. The solution is then poured into water (30 mL),extracted with ethyl acetate (3×50 mL) and the combined organic extractswashed with brine (30 mL), dried (magnesium sulfate), and concentratedto give a yellow-brown oil. The oil is subjected to mplc on silica gel,using petroleum ether: ethyl acetate (3:1 v/v) as eluent to give2-(3,5-dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanone(0.14 g). m.p. 115-116.5° C. [Elemental analysis:—C, 57.7; H, 4.7; N,3.5%. calculated:—C, 57.3; H, 4.6; N, 3.5%].

EXAMPLE 14 Compounds CI-CN

A stirred solution ofN-(3,5-dichloropyrid-4-yl)-2-fluoro-5-isopropyloxy-4-methoxybenzamide(0.5 g) in glacial acetic acid (10 mL) is treated dropwise with anaqueous solution of hydrogen peroxide (2 ml; 27.5%). The mixture isstirred for 3 hours at 70-80° C., treated with a further portion ofaqueous hydrogen peroxide (2 mL), and the solution stirred for a further12 hours. The solution is then cooled, basified by treatment with 2 Nsodium hydroxide solution (50 mL) and extracted with ethyl acetate(3×150 mL). The combined organic extracts are washed with brine (50 mL),dried (magnesium sulfate) and concentrated to give a brown oil. The oilis subjected to mplc on silica gel using ether as eluent to giveN-(3,5-dichloro-1-oxido-4-pyridinio)-2-fluoro-5-isopropyloxy-4-methoxybenzamide(0.25 g). m.p. 142-144° C. [Elemental analysis:—C, 48.6; H, 3.9; N, 7.0;Cl, 17.6%. calculated:—C, 48.3; H, 4.05; N, 7.0; Cl, 17.8%].

By proceeding in a similar manner, but using the appropriate quantitiesof the appropriate benzamide or ethanone there are prepared:—

(±)N-(3,5-dichloro-1-oxido-4-pyridinio)-3-exonorbornyloxy-6-fluoro-4-methoxybenzamide,m.p. 101-106° C. [Elemental analysis:—C, 53.9; H, 4.5; N, 6.3; Cl,15.5%. calculated:—C, 53.9; H, 4.4; N, 6.3; Cl, 15.9%].

N-(3,5-dichloro-1-oxido-4-pyridinio)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide,m.p. 143-144° C. [Elemental analysis:—C, 52.9; H, 4.5; N. 6.4; Cl,16.2%. calculated:—C, 52.1; H, 4.1; N, 6.75; Cl, 17.1%].

N-(3,5-dichloro-1-oxido-4-pyridinio)-3-cyclopentyloxy-4-difluoromethoxy-6-fluorobenzamide,m.p. 129-130° C. [Elemental analysis:—C, 47.6; H, 3.4; N, 6.0; Cl,15.3%. calculated:—C, 47.9; H, 3.35; N, 6.2; Cl, 15.7%].

N-(3,5-dichloro-1-oxido-4-pyridinio)-4-difluoromethoxy-2-fluoro-5-isopropyloxybenzamide,m.p. 196-198° C. [Elemental analysis:—C, 45.2; H, 3.0; N, 6.5; Cl,16.6%. calculated:—C, 45.2; H, 3.1; N, 6.6; Cl, 16.7%].

2-(3,5-Dichloro-1-oxido-4-pyridinio)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanone,m.p. 159-162° C. [Elemental analysis:—C, 54.9; H, 4.4; N, 3.5; Cl,16.9%. calculated:—C, 55.1; H, 4.4; N, 3.4; Cl, 17.1%].

EXAMPLE 15 Compound CO

Thionyl chloride (0.78 mL) is added to a solution of5-cyclopentyloxy-6-methoxynicotinic acid (850 mg) and dimethylformamide(1 drop) in toluene (60 mL). The mixture is heated and stirred at refluxfor 1 hour. The mixture is cooled and concentrated to give crude acidchloride.

Meanwhile, sodium hydride (320 mg of a 60% dispersion in oil) is addedto a stirred solution of 4-amino-3,5-dichloropyridine (649 mg) in drydimethylformamide (20 mL) under a nitrogen atmosphere. The mixture isstirred at room temperature for 30 minutes. The crude acid chloride isdissolved in dry dimethylformamide (10 mL) and the solution is addeddropwise to the mixture. After 3 hours, the mixture is diluted withwater and the mixture extracted with ethyl acetate. The ethyl acetateextracts are washed with water and dried (MgSO₄). Concentration of theextracts gave a buff solid which is triturated with methyl t.butyl etherto give5-cyclopentyloxy-N-(3,5-dichloropyrid-4-yl)-6-methoxynicotinamide (500mg) as a white solid, m.p. 182-183° C. [Elemental analysis:—C, 53.4; H,4.45; Cl, 18.6; N, 10.9%. calculated:—C, 53.4; H, 4.48; Cl, 18.55; N,10.99%.]

EXAMPLE 16 Compound CP

Thionyl chloride (0.46 mL) is added to a solution of5-cyclopentyloxy-6-methoxynicotinic acid (500 mg) and dimethylformamide(1 drop) in toluene (10 mL). The mixture is heated and stirred at refluxfor 1 hour. The mixture is cooled and concentrated to give crude acidchloride as a yellow oil which slowly crystallised.

Meanwhile, sodium hydride (128 mg of a 60% dispersion in oil) is addedto a stirred solution of 2,6-dichloroaniline (263 mg) in drytetrahydrofuran (10 mL) under a nitrogen atmosphere. The mixture isstirred at room temperature for 45 minutes. The crude acid chloride isdissolved in dry tetrahydrofuran (5 mL) and the resulting solution addeddropwise to the mixture. After 3 hours the mixture is concentrated,treated with water, and extracted with ethyl acetate. The extracts aredried (MgSO₄) and concentrated to give a brown oil. Trituration of theoil with methyl t.butyl ether gaveN-(2,6-dichlorophenyl)-5-cyclopentyloxy-6-methoxynicotinamide (250 mg)as a white solid, m.p. 145-6° C. [Elemental analysis:—C, 56.7; H, 4.79;Cl, 18.5; N, 7.4%. calculated:—C, 56.7; H, 4.76; Cl, 18.6; N, 7.35%.]

EXAMPLE 17 Compound CQ

Thionyl chloride (0.46 mL) is added to a solution of5-cyclopentyloxy-6-methoxynicotinic acid (500 mg) and dimethylformamide(1 drop) in toluene (10 mL). The mixture is heated and stirred at refluxfor 1 hour. The mixture is cooled, concentrated, and the residuedissolved in dichloromethane (5 mL). This solution is added dropwise toa solution of 4-amino-3,5-dimethylisoxazole (168 mg) and triethylamine(0.21 mL) in dichloromethane (20 mL). The resulting mixture is stirredat room temperature for 2 hours then at reflux for 1 hour. The cooledmixture is washed with water, 2 M aqueous hydrochloric acid, water, thendried (MgSO₄). After concentration the yellow oily residue is trituratedwith a mixture of n-pentane and methyl t.butyl ether to give5-cyclopentyloxy-N-(3,5-dimethylisoxazol-4-yl)-6-methoxynicotinamide(240 mg) as a buff solid, m.p. 139-40° C. [Elemental analysis:—C, 61.3;H, 6.40; N, 12.4%. calculated:—C, 61.6; H, 6.39; N, 12.68%.]

EXAMPLE 18 Compound CR

Thionyl chloride (0.46 mL) is added to a solution of5-cyclopentyloxy-6-methoxynicotinic acid (500 mg) and dimethylformamide(1 drop) in toluene (10 mL). The mixture is heated and stirred at refluxfor 1 hour. The mixture is cooled and concentrated to give crude acidchloride.

Meanwhile, sodium hydride (128 mg of a 60% dispersion in oil) is addedto a stirred solution of 4-amino-3,5-difluoropyridine (208 mg) in drytetrahydrofuran (10 mL) under a nitrogen atmosphere. The mixture isstirred at room temperature for 60 minutes. The crude acid chloride isdissolved in dry tetrahydrofuran (5 mL) and the resulting solution addeddropwise to the mixture. After 3 hours the mixture is treated with waterand concentrated. The residue is diluted with water and the mixtureextracted with ethyl acetate. The extracts are dried (MgSO₄) andconcentrated to give a white solid. The solid is triturated withn-pentane and methyl t-butyl ether to give5-cyclopentyloxy-N-(3,5-difluoropyrid-4-yl)-6-methoxynicotinamide (230mg), as a white solid, m.p. 210-11° C. [Elemental analysis:—C, 58.4; H,4.93; N, 11.8%. calculated:—C, 58.45; H, 4.91; N, 12.03%.]

EXAMPLE 19 Compound CS

Thionyl chloride (0.45 mL) is added to a solution of6-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (510 mg) anddimethylformamide (1 drop) in toluene (6 mL). The mixture is heated andstirred at reflux for 2.5 hours. The mixture is cooled and concentratedto give crude acid chloride.

Meanwhile, sodium hydride (51 mg of a 60% dispersion in oil) is added toa stirred solution of 4-amino-3,5-dichloropyridine (350 mg) in drytetrahydrofuran (10 mL) under a nitrogen atmosphere. The mixture isstirred at room temperature for 30 minutes. The crude acid chloride isdissolved in dry tetrahydrofuran (6 mL) and the resulting solution addeddropwise to the mixture. The mixture is stirred for 4.5 hours and thenallowed to stand at room temperature for 72 hours. The mixture istreated with water, concentrated and the residue extracted with ethylacetate. After washing with water the extracts are dried (MgSO₄) andconcentrated. The residue is purified by flash chromatography (alumina,pentane/ethyl acetate 9:1 v/v as eluent) to give6-cyclopentyloxy-N-(3,5-dichloropyrid-4-yl)-5-methoxypyridine-2-carboxamide(750 mg) as a white solid, m.p. 164-6° C. [Elemental analysis:—C, 53.6;H, 4.56; Cl, 18.4; N, 11.2%. calculated:—C, 53.4; H, 4.48; Cl, 18.55; N,10.99%.]

EXAMPLE 20 Compound CT

n-Butyl lithium (4.9 mL of a 2.5M solution in hexanes) is added dropwiseto a stirred solution of diisopropylamine (1.7 mL) in drytetrahydrofuran (20 mL) at −78° C. under a nitrogen atmosphere. After 30minutes. a solution of 3,5-dichloro-4-methylpyridine (1.95 g) in drytetrahydrofuran (10 mL) is added dropwise and the solution stirred at−78° C. for a further 30 minutes. A solution of methyl5-cyclopentyloxy-6-methoxynicotinoate (1.5 g) in dry tetrahydrofuran (15mL) is added and the red mixture stirred and allowed to warm to roomtemperature during 4 hours. After stirring overnight at room temperaturethe mixture is treated with saturated aqueous ammonium chloride. Thetetrahydrofuran layer is separated and the aqueous phase is extractedwith ethyl acetate. The combined organic layers are washed with salineand dried over anhydrous magnesium sulphate. Concentration gives a lightbrown oil which is triturated with a mixture of n-pentane and methylt-butyl ether to give1-(5-cyclopentyloxy-6-methoxypyridin-3-yl)-2-(3,5-dichloropyrid-4-yl)ethanone(1 g) in the form of a beige solid, m.p. 118-9° C. [Elementalanalysis:—C, 56.8; H, 4.82; Cl, 18.5; N, 7.40%. calculated:—C, 56.7; H,4.76; Cl, 18.6; N, 7.35%.]

EXAMPLE 21 Compound CU

Thionyl chloride (0.55 mL) is added to a solution of5-cyclopentyloxy-6-methylthionicotinic acid (0.6 g) in dry toluene (10mL) containing dimethylformamide (1 drop) and the mixture stirred atreflux for 1.5 hours. The solution is evaporated in vacuo, redissolvedin toluene and evaporated again to give the crude acid chloride.

Meanwhile sodium hydride (220 mg of a 60% dispersion in mineral oil) isadded to a stirred solution of 4-amino-3,5-dichloropyridine (445 mg) indry tetrahydrofuran (10 mL) under an atmosphere of nitrogen, and themixture is stirred at room temperature for 1 hour. The crude acidchloride is dissolved in tetrahydrofuran (10 mL) and added to themixture and the mixture stirred at room temperature for 3 hours. Themixture is evaporated, the residue diluted with water and the productextracted into ethyl acetate. The extracts are dried (MgSO₄),evaporated, and triturated with a mixture of n-pentane and t-butylmethyl ether to give5-cyclopentyloxy-N-(3,5-dichloro-4-pyridyl)-6-methylthionicotinamide(500 mg) as a cream solid, m.p. 144-5° C. [Elemental analysis:—C, 51.50;H, 4.42; Cl, 17.7; N, 10.5; S, 8.1%. calculated:—C, 51.26; H, 4.30; Cl,17.8; N, 10.55; S, 8.05%].

EXAMPLE 22 Compound CV

By proceeding in a similar manner to example 21 but replacing the5-cyclopentyloxy-6-methylthionicotinic acid by the appropriate quantityof 5-isopropyloxy-6-methylthionicotinic acid there is obtained:—

N-(3,5-dichloro-4-pyridyl)-5-isopropyloxy-6-methylthionicotinamide as awhite solid, m.p. 167-8° C. [Elemental analysis:—C, 48.20; H, 4.02; Cl,19.30; N, 11.30%. calculated:—C, 48.40; H, 4.06; Cl, 19.05; N, 11.29%].

EXAMPLE 23 Compound CW

n-Butyl lithium (3.73 mL of a 2.5 M solution in hexanes) is addeddropwise to a stirred solution of diisopropylamine (1.29 mL) in drytetrahydrofuran (15 mL) at −75° C. under a nitrogen atmosphere. Afterstirring for 30 minutes, a solution of 3,5-dichloro-4-methylpyridine(1.48 g) in dry tetrahydrofuran (8 mL) is added dropwise and the mixturestirred for a further 30 minutes. A solution of methyl5-isopropyloxy-6-methylthionicotinoate (1.1 g) in dry tetrahydrofuran(10 mL) is added dropwise at −75° C. and the mixture allowed to warm toroom temperature during 4 hours. The reaction is quenched by theaddition of saturated aqueous ammonium chloride and then the solvent isremoved in vacuo. The aqueous residue is extracted with ethyl acetate,the extracts washed with water and dried (MgSO₄). After treating withdecolourising charcoal and removing the solvent, a dark yellow oil isobtained. The oil is dissolved in a minimum amount of n-pentane/methylt-butylether and allowed to crystallise.2-(3,5-dichloro-4-pyridyl)-1-(5-isopropyloxy-6-methylthio-3-pyridyl)ethanone(450 mg) is obtained as a white solid, m.p. 124-5° C. [Elementalanalysis:—C, 51.8; H, 4.34; Cl, 19.10; N, 7.50%. calculated:—C, 51.76;H, 4.34; Cl, 19.10; N, 7.55%].

EXAMPLE 24 Compound CX

Hydrogen peroxide (3 mL of strength 27.5%) is added to a stirredsuspension of1-(5-cyclopentyloxy-6-methoxypyrid-3-yl)-2-(3,5-dichloropyrid-4-yl)ethanone(470 mg) in glacial acetic acid (5 mL) and the mixture heated at 75±5°C. for 3 hours. More hydrogen peroxide (1 mL of strength 27.5%) is addedand the mixture heated for a further 2 hours. After cooling, the mixtureis basefied with 6 M aqueous sodium hydroxide and extracted with ethylacetate. The extracts are washed with water, dried (MgSO₄) andevaporated. The residue is triturated with diethyl ether to afford1-(5-cyclopentyloxy-6-methoxypyrid-3-yl)-2-(3,5-dichloro-1-oxido-4-pyridinio)ethanonehemihydrate (100 mg) as a white solid, m.p. 171-2° C. [Elementalanalysis:—C, 53.5; H, 4.51; N, 7.0%. calculated:—C, 53.20; H, 4.71; N,6.90%].

EXAMPLE 25 Compounds CY-CZ

Diisopropyl azodicarboxylate (1.67 mL) is added to a stirred solution oftriphenylphosphine (2.22 g) in dry tetrahydrofuran (20 mL) at 0-5° C.under a nitrogen atmosphere. After 30 minutes, methyl5-hydroxy-6-methoxynicotinoate (1.55 g) and a solution of a mixture of(±)-endo- and (±)-exo-(8,9,10-trinorborn-5-en-2-ol) (0.94 g) in drytetrahydrofuran (5 mL) are added successively and the mixture refluxedfor 24 hours. After cooling to room temperature the mixture is dilutedwith water and extracted with ethyl acetate. The extracts are washedwith water, dried (MgSO₄) and evaporated.

Purification by Flash Chromatography

(n-pentane/ethyl acetate 9:1 v/v on silica) affords a mixture of methyl(±)-6-methoxy-5-exo-(8,9,10-trinorborn-5-en-2-yloxy)nicotinoate andmethyl(±)-6-methoxy-5-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)nicotinoate, (950mg) [Elemental analysis:—C, 65.50; H, 6.35; N, 5.14%. calculated:—C,65.44; H, 6.22; N, 5.09%].

The mixture of methyl(±)-6-methoxy-5-exo(8,9,10-trinorborn-5-en-2-yloxy)nicotinoate andmethyl(±)-6-methoxy-5-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)nicotinoate, (900mg), dissolved in methanol (20 mL) is treated with a solution ofpotassium hydroxide (380 mg) in water (5 mL) and stirred at 45° C. for 3hours. After cooling the bulk of the solvent is removed in vacuo, theresidue dissolved in water and the solution acidified to pH 2 withconcentrated aqueous hydrochloric acid. The products are extracted intoethyl acetate, the extracts dried (MgSO₄) and evaporated to give amixture of (±)-6-methoxy-5-exo (8,9,10-trinorborn-5-en-2-yloxy)nicotinicacid and(±)-6-methoxy-5-(tricyclo[2.2.1.0.^(2.6.)]-hept-2-yloxy)nicotinic acid,(670 mg), as a white solid. [Elemental analysis:—C, 64.50; H, 5.76; N,5.53%. calculated:—C, 64.36; H, 5.79; N, 5.36%].

The mixture of(±)-6-methoxy-5-exo-(8,9,10-trinorborn-5-en-2-yloxy)nicotinic acid and(±)-6-methoxy-5-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)nicotinic acid,(670 mg), is stirred in a mixture of dichloromethane (10 mL) anddimethylformamide (1 drop) and oxalyl chloride (487 mg) is added and theresulting mixture stirred at room temperature for 30 minutes. Themixture is concentrated in vacuo to give a mixture of the acidchlorides.

Meanwhile sodium hydride (160 mg of a 60% dispersion in mineral oil) isadded to a solution of 4-amino-3,5-dichloropyridine (445 mg) in drytetrahydrofuran (10 mL) under a nitrogen atmosphere. The mixture isstirred for 30 minutes at room temperature and then a solution of theforegoing mixture of acid chlorides in dry tetrahydrofuran (5 mL) isadded and stirring is continued for a further 3 hours. The reactionmixture is evaporated, the residue diluted with water and extracted intoethyl acetate. The extracts are dried (MgSO₄) and evaporated to give apale yellow oil. The oil is partially purified by flash chromatography(n-pentane/ethyl acetate 4:1 v/v as eluent on silica) to give a mixtureof(±)—N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-exo(8,9,10-trinorborn-5-en-2-yloxy)nicotinamideand(±)-N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)nicotinamide,(340 mg), as a white solid. This mixture is purified into the individualconstituents by reversed phase high pressure liquid chromatography togive(±)—N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-exo-(8,9,10-trinorborn-5-en-2-yloxy)nicotinamide(195 mg) as a white solid, m.p. 191-3° C., [¹Hnmr in D₆-DMSO shiftsrelative to Me₄Si:—1.42, 1H, m; 1.56, 1H, m; 1.75, 1H, m; 1.81, 1H, m;2.91, 1H, m; 3.03, 1H, m; 3.96, 3H, s; 6.07, 1H, m; 6.35, 1H, m; 7.70,1H, d; 8.42, 1H, d; 8.77, 2H, s; 10.61, 1H, br. s.]. [Elementalanalysis:—C, 55.9; H, 4.24; N, 10.2%. calculated:—C, 56.17; H, 4.22; N,10.34%], and(±)—N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)nicotinamidemonohydrate (74 mg) as a white crystalline solid, m.p. 213-4° C. [¹ Hnmrin D₆-DMSO shifts relative to Me₄Si: —1.30, 2H, m; 1.36, 3H, m; 1.55,1H, m; 1.83, 1H, m; 2.16, 1H, m; 3.96, 3H, s; 4.49, 1H, m; 7.78, 1H, d;8.42, 1H, d; 8.77, 2H, s; 10.62, 1H, br. s.]. [Elemental analysis:—C,53.5; H, 4.01; N, 9.70%. calculated:—C, 53.79; H, 4.51; N, 9.90%].

EXAMPLE 26 Compounds DA-FE

Thionyl chloride (0.5 mL) is added to a stirred mixture of4-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (500 mg) in drytoluene (10 mL) containing dimethylformamide (1 drop). The mixture isstirred at gentle reflux for 1 hour, cooled and concentrated in vacuo togive the acid chloride, which is dissolved in dimethylformamide (10 mL).

Meanwhile sodium hydride (160 mg of a 60% dispersion in mineral oil) isadded to a solution of 4-amino-3,5-dichloropyridine (665 mg) in drydimethylformamide (10 mL), the mixture stirred for 1 hour and then addedto the solution of the acid chloride. The resulting mixture is stirredfor 6 hours, concentrated in vacuo, the residue diluted with water andthe product extracted into ethyl acetate. The dried (MgSO₄) extracts areconcentrated to a yellow/brown solid which is purified by flashchromatography (dichloromethane/methanol 50:1 v/v as eluent on silica)to giveN-(3,5-dichloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide,(220 mg) as a white solid, m.p. 129-30° C. [Elemental analysis:—C, 53.1;H, 4.44; N, 11.1%. calculated:—C, 53.42; H, 4.48; N, 10.99%].

By proceeding in a similar manner, but replacing4-amino-3,5-dichloropyridine by the appropriate quantities of thecorresponding aniline or aminopyridine derivatives and acid chloridesthere are prepared:

-   N-(2,6-difluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2-chloro-6-fluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2,4,6-trichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2,6-dibromophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2-chloro-6-methylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2,6-dichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2-fluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-phenyl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2-chlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(3-chlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(4-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2,6-dimethylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2-methylthiophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2-bromophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2-methoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2-aminosulfonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2-benzoylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2-cyanophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2,5-dichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(3-methylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2-dimethylaminophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2-acetylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2-hydroxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(4-chloropyrid-3-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-pyrid-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-pyrazin-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-pyrimidin-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(3-methylpyrid-2-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-pyrid-3-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(3-chloropyrid-2-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(3-chloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-pyrid-4-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(3,5-dimethylisoxazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(3,5-dibromopyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(3,5-dimethylpyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2,6-dichloro-4-cyanophenyl)-4-cyclopentoxy-5-methoxypyridine-2-carboxamide;-   N-(2,6-dichloro-4-methoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2,3,5-trifluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2,6-dichloro-4-ethoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2,6-dichloro-4-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(3,5-difluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(3-bromo-5-chloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2,4,6-trifluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2,6-dichloro-4-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(4,6-dichloropyrmid-5-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2,3,5,6-tetrafluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(3,5-dichloro-2,6-difluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(5-cyano-3-methylisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(2,6-dichloro-4-carbamoylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(3-chloro-2,5,6-trifluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(4-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;-   N-(3-methyl-5-bromoisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;    and-   N-(3,5-dimethylisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide.

EXAMPLE 27 Compound FF

A mixture ofN-(3,5-dichloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide(360 mg) and aqueous hydrogen peroxide (3 mL of strength 27.5%) inglacial acetic acid is heated at 75±5° C. for 3 hours. After cooling,the mixture is basefied with 6 M aqueous sodium hydroxide and extractedwith ethyl acetate. The extracts are washed with water, dried (MgSO₄)and evaporated to give a white solid. The solid is purified by flashchromatography (gradient elution with pentane/ethyl acetate 7:3 v/vchanging to pentane/ethyl acetate 1:1 v/v on silica) to giveN-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamideas a white solid, m.p. 206-7° C. [Elemental analysis:—C, 51.6; H, 4.37;N, 10.40%. calculated: —C, 51.27; H, 4.30; N, 10.55%].

EXAMPLE 28 Compound FG

Oxalyl chloride (50 mL) in dry dichloromethane (1.5 mL) is cooled to−30° C. under a nitrogen atmosphere. Dimethyl sulphoxide (80 mL) isadded, the mixture stirred for 10 minutes then a solution of(±)-1-(4-cyclopentyloxy-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanol(210 mg) in dichloromethane (2.5 mL) is added and the mixture stirredfor 3 hours. Triethylamine (0.2 mL) is added and the mixture is allowedto warm to room temperature. After pouring into water the organic phaseis extracted into dichloromethane, the extracts washed sequentially with1% aqueous sulphuric acid, water, saturated aqueous sodium bicarbonateand water. The extracts are dried (MgSO₄) and evaporated to give asolid. The solid is triturated with pentane, collected and dried to give1-(4-cyclopentyloxy-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanone(60 mg), as an off-white solid, m.p. 132° C. [Elemental analysis:—C,56.80; H, 4.92; N, 7.10%. calculated:—C, 56.71; H, 4.78; N, 7.35%].

EXAMPLE 29 Compounds FH-FI

Thionyl chloride (0.4 mL) is added to a stirred solution of(±)-6-methoxy-5-exo(8,9,10-trinorborn-2-yloxy)nicotinic acid (0.4 g) intoluene (10 mL) containing dimethylformamide (1 drop). The mixture isrefluxed for 1 hour, cooled and evaporated to give the acid chloridewhich is dissolved in dimethylformamide (10 mL).

Meanwhile sodium hydride (80 mg of a 60% dispersion in mineral oil) isadded to a solution of 4-amino-3,5-difluoropyridine (0.26 g) indimethylformamide (10 mL) and the mixture stirred for 1 hour. Themixture is then added to the solution of the acid chloride and stirringcontinued for 6 hours. After evaporation of the solvent the residue ispartitioned between ethyl acetate and water. The ethyl acetate phase isseparated, washed with water, dried (MgSO₄) and evaporated to give anoil. The oil is purified by flash chromatography (n-pentane/ethylacetate3:2 v/v as eluent on silica) to give an oil which upon triturating withn-pentane gave(±)—N-(3,5-difluoropyrid-4-yl)-6-methoxy-5-exo(8,9,10-trinorborn-2-yloxy)nicotinamide,(0.19 g) as a solid, m.p. 120-1° C. [Elemental analysis:—C, 61.3; H,5.33; N, 11.3%. calculated:—C, 60.80; H, 5.10; N, 11.19%].

By proceeding in a similar manner, but replacing4-amino-3,5-difluoropyridine with the appropriate quantity of4-amino-3,5-dichloropyridine, there is prepared:—

(±)—N-(3,5-dichloropyridin-4-yl)-6-methoxy-5-exo(8,9,10-trinorborn-2-yloxy)nicotinamide,m.p. 169-170° C. [Elemental analysis:—C, 55.90; H, 4.73; N, 10.30%.calculated:—C, 55.90; H, 4.69; N, 10.29%].

EXAMPLE 30 Compounds FJ-FN

Thionyl chloride (0.65 mL) is added to a stirred solution of(±)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxylicacid (0.4 g) in toluene (10 mL) containing dimethylformamide (1 drop).The mixture is refluxed for 2 hours, cooled and evaporated to give theacid chloride which is dissolved in dimethylformamide (5 mL).

Meanwhile sodium hydride (116 mg of a 60% dispersion in mineral oil) isadded to a solution of N-(3,5-dichloropyridin-4-yl)acetamide (449 mg) indimethylformamide (15 mL) and the mixture stirred for 2 hours. Themixture is then added to the solution of the acid chloride and stirringcontinued for 3 hours. After evaporation of the solvent the residue ispartitioned between ethyl acetate and water. The ethyl acetate phase isseparated, washed with water, dried (MgSO₄) and evaporated to give abrown oil. The oil is diluted with dimethylformamide (10 mL) and treatedwith piperidine (0.61 mL) for 18 hours. After concentrating the residueis partitioned between water and ethyl acetate. The ethyl acetate phaseis washed with water, dried (MgSO₄) and evaporated. The residue ispurified by flash chromatography (n-pentane/ethylacetate 7:3 v/v aseluent on silica) to give(±)—N-(3,5-dichloropyrid-4-yl)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxamide,(0.35 g) as a white solid, m.p. 161-2° C. [Elemental analysis:—C, 56.14;H, 4.29; Cl, 17.67; N, 10.13%. calculated:—C, 56.17; H, 4.22; Cl, 17.45;N, 10.34%].

By proceeding in a similar manner, but replacing4-amino-3,5-dichlororopyridine with the appropriate quantity of4-amino-3,5-difluoropyridine, there is prepared:—

(±)—N-(3,5-difluoropyrid-4-yl)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxamidehydrate, m.p. 64-5° C. [Elemental analysis: —C, 60.34; H, 4.63; N,1.18%. calculated:—C, 60.39; H, 4.67; N, 11.12%].

By proceeding in a similar manner, but replacing(±)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxylicacid with the appropriate quantity of(±)-5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxylic acid,there is prepared:—

(±)—N-(3,5-dichloropyridin-4-yl)-5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxamide,m.p. 171-2° C. [Elemental analysis:—C, 48.4; H, 3.88; N, 10.63%.calculated:—C, 48.01; H, 3.78; N, 10.50%].

By proceeding in a similar manner, but replacing(±)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxylicacid with the appropriate quantity of4-cyclopropylmethoxy-5-methoxypyridine-2-carboxylic acid, there isprepared:—

N-(3,5-dichloropyridin-4-yl)-4-cyclopropylmethoxy-5-methoxypyridine-2-carboxamide,m.p. 132-132.5° C. [Elemental analysis:—C, 52.12; H, 4.12; Cl, 19.03; N,11.40%. calculated:—C, 52.19; H, 4.11; Cl, 19.26; N, 11.41%].

By proceeding in a similar manner, but replacing(±)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxylicacid with the appropriate quantity of4-isopropyloxy-5-methoxypyridine-2-carboxylic acid, there is prepared:—

N-(3,5-dichloropyridin-4-yl)-4-isopropyloxy-5-methoxypyridine-2-carboxamide,m.p. 142-3° C. [Elemental analysis:—C, 50.3; H, 4.20; Cl, 20.10; N,11.85%. calculated:—C, 50.58; H, 4.25; Cl, 19.91; N, 11.80%].

EXAMPLE 31 Compounds FO-FS

Thionyl chloride (0.84 mL) is added to a stirred solution of(±)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxylicacid (0.7 g) in toluene (10 mL) containing dimethylformamide (1 drop).The mixture is refluxed for 2 hours, cooled and evaporated to give theacid chloride which is dissolved in dimethylformamide (5 mL).

Meanwhile sodium hydride (150 mg of a 60% dispersion in mineral oil) isadded to a solution of N-(3,5-dichloro-1-oxido-4-pyridinio)acetamide(663 mg) in dimethylformamide (20 mL) and the mixture stirred for 2hours. The mixture is then added to the solution of the acid chlorideand stirring continued for 3 hours. Piperidine (0.26 mL) is added andstirring continued for a further 4 hours. After concentrating in vacuothe residue is dissolved in dichloromethane, the mixture filtered, thefiltrate treated with decolourising charcoal and refiltered. Evaporationin vacuo gives a brown oil which is purified by reverse phase highpressure liquid chromatography (methanol/water 4:1 v/v) to give(±)—N-(3,5-dichloro-1-oxido-4-pyridinio)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxamide(60 mg) as a solid, m.p. 235-6° C. [Elemental analysis:—C, 54.16; H,4.21; N, 10.58%. calculated:—C, 56.04; H, 4.06; N, 9.95%].

By proceeding in a similar manner, but replacingN-(3,5-dichloro-1-oxido-4-pyridinio)acetamide with the appropriatequantity of N-(3,5-difluoro-1-oxido-4-pyridinio)acetamide, there isprepared:—

(±)—N-(3,5-difluoro-1-oxido-4-pyridinio)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxamide,m.p. 290° C. [Elemental analysis:—C, 58.27; H, 4.57; N, 10.58%.calculated:—C, 58.61; H, 4.40; N, 10.79%].

By proceeding in a similar manner, but replacing(±)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxylicacid with the appropriate quantity of4-isopropyloxy-5-methoxypyridine-2-carboxylic acid, there is prepared:—

N-(3,5-dichloro-1-oxido-4-pyridinio)-4-isopropyloxy-5-methoxypyridine-2-carboxamide,m.p. 220-1° C. [Elemental analysis:—C, 48.65; H, 4.10; Cl, 19.24; N,11.40%. calculated:—C, 48.40; H, 4.06; Cl, 19.05; N, 11.29%].

By proceeding in a similar manner, but replacing(±)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxylicacid with the appropriate quantity of4-cyclopropylmethoxy-5-methoxypyridine-2-carboxylic acid, there isprepared:—

N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxypyridine-2-carboxamidehemihydrate, m.p. 206-8° C. [Elemental analysis:—C, 49.12; H, 3.94; Cl,18.04; N, 10.61%. calculated:—C, 48.87; H, 4.11; Cl, 18.03; N, 10.69%].

By proceeding in a similar manner, but replacing(±)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxylicacid with the appropriate quantity of(±)-5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxylic acid,there is prepared:—

(±)—N-(3,5-dichloro-1-oxido-4-pyridinio)-5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxamide,m.p. 223-5° C. [Elemental analysis:—C, 45.90; H, 3.61; Cl, 17.23; N,10.07%. calculated:—C, 46.16; H, 3.63; Cl, 17.03; N, 10.09%].

EXAMPLE 32 Compounds FT-FV

3-Chloroperoxybenzoic acid (2.16 g, of 50-60% grade peracid) is added toa solution ofN-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide(0.8 g) in dichloromethane (80 mL) and the mixture refluxed for 8 hours.Another quantity of 3-chloroperoxybenzoic acid (0.5 g, of 50-60% gradeperacid) is added and refluxing continued for 1 hour. After cooling themixture is washed with saturated aqueous sodium bicarbonate, dried(MgSO₄) and evaporated. The residue is purified by flash chromatography(ethyl acetate/methanol 19:1 v/v as eluent on silica) to giveN-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-methoxy-1-oxidopyridinium-2-carboxamide,(740 mg), as an off-white solid, m.p. 154.5-155.5° C. [Elementalanalysis:—C, 49.44; H, 4.17; Cl, 17.04; N, 10.07%. calculated: —C,49.29; H, 4.14; Cl, 17.12; N, 10.14%].

By proceeding in a similar manner, but replacingN-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamidewith the appropriate quantity ofN-(3,5-dichloropyridin-4-yl)-4-cyclopropylmethoxy-5-methoxypyridine-2-carboxamide,there is prepared:—

N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxy-1-oxidopyridinium-2-carboxamide,m.p. 239-40° C. [Elemental analysis:—C, 48.2; H, 3.93; N, 10.13%.calculated:—C, 48.01; H, 3.78; N, 10.53%].

By proceeding in a similar manner, but replacingN-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamidewith the appropriate quantity ofN-(3,5-dichloropyridin-4-yl)-4-isopropyloxy-5-methoxypyridine-2-carboxamide,there is prepared:—

N-(3,5-dichloro-1-oxido-4-pyridinio)-4-isopropyloxy-5-methoxy-1-oxidopyridinium-2-carboxamide,m.p. 236-8° C. [Elemental analysis:—C, 46.38; H, 3.91; N, 10.48%.calculated:—C, 46.41; H, 3.89; N, 10.82%].

EXAMPLE 33 Compounds FW-FX

n-Butyllithium (10.6 mL of a 1.6 M solution in hexane) is added dropwiseto a stirred solution of diisopropylamine (2.55 mL) in tetrahydrofuran(30 mL) at −78° C. under a nitrogen atmosphere. After stirring for 30minutes a solution of 3,3-dichloro-4-methylpyridine (2.93 g) intetrahydrofuran (15 mL) is added. After a further 30 minutes theresulting yellow suspension is treated with a solution of (±)-methyl5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxylate(2.32 g) in tetrahydrofuran (25 mL), stirred for 30 minutes at −78° C.then allowed to warm to room temperature during 4 hours. After standingovernight the mixture is treated with aqueous ammonium chloride and thebulk of the tetrahydrofuran removed in vacuo. The residue is dilutedwith water and extracted with ethyl acetate. The extracts are washedwith saline, dried (MgSO₄) and evaporated to give an oil. The oil ispurified by flash chromatography (n-pentane/ethyl acetate 4:1 v/v eluenton silica) to give1-(5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanone(1.0 g), as a white solid, m.p. 156-7° C. [Elemental analysis:—C, 59.10;H, 4.34; Cl, 17.37; N, 7.04%. calculated:—C, 59.27; H, 4.48; Cl, 17.50;N, 6.91%].

By proceeding in a similar manner, but replacing (±)-methyl5-methoxy-4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)pyridine-2-carboxylatewith the appropriate quantity of (±)-methyl5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxylate, there isprepared:—

(±)-1-(5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanoneas a white solid, m.p. 168-70° C. [Elemental analysis:—C, 51, 16; H,4.06; Cl, 17.68; N, 7.04%. calculated:—C, 51.14; H, 4.04; Cl, 17.76; N,7.02%].

EXAMPLE 34 Compound FY

A solution of(±)-1-(4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanone(340 mg) in dichloromethane (20 mL) is treated with 3.63 mL of asolution of 50% m-chloroperbenzoic acid (2 g) in dichloromethane (25mL). The mixture is stirred at room temperature for 2 hours thenrefluxed for 6 hours. After cooling to room temperature the mixture iswashed with saturated aqueous sodium bicarbonate, dried (MgSO₄) andevaporated to give a yellow solid. The solid is purified by flashchromatography (gradient elution pentane/ethyl acetate 7:3 v/v to neatethyl acetate on silica) to give1-(4-(tricyclo[2.2.1.0.^(2.6.)]hept-2-yloxy)-5-methoxypyridin-2-yl)-2-(3,5-dichloro-1-oxido-4-pyridinio)ethanone(160 mg) as a white solid, m.p. 196-8° C. [Elemental analysis:—C, 57.15;H, 4.47; N, 6.59% calculated:—C, 57.02; H, 4.31; N, 6.65%].

EXAMPLE 35 Compounds FZ-GA

Diphosphorus tetraiodide (53 mg) is added to a stirred solution ofN-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxy-1-oxidopyridinium-2-carboxamide(150 mg) in dichloromethane (3 mL) under a nitrogen atmosphere. Thebrown solution is stirred for 10 minutes and the inorganic decomposed bythe addition of aqueous sodium sulphite. The mixture is made alkaline bythe addition of 30% aqueous sodium hydroxide. The dichloromethane layeris separated and the aqueous phase extracted with dichloromethane. Thecombined dichloromethane phases are dried (MgSO₄) and evaporated to givea white solid. The solid is purified by flash chromatography (ethylacetate as eluent on silica) to affordN-(3,5-dichloropyridin-4-yl)-4-cyclopropylmethoxy-5-methoxy-1-oxidopyridinium-2-carboxamide(80 mg) as a white solid, m.p. 178-80° C. [Elemental analysis: —C,49.97; H, 3.94; N, 10.94%. calculated:—C, 50.01; H, 3.94; N, 10.94%].

By proceeding in a similar manner, but replacingN-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxy-1-oxidopyridinium-2-carboxamidewith the appropriate quantity ofN-(3,5-dichloro-1-oxido-4-pyridinio)-4-isopropyloxy-5-methoxy-1-oxidopyridinium-2-carboxamide,there is prepared:—

N-(3,5-dichloropyridin-4-yl)-4-isopropyloxy-5-methoxy-1-oxidopyridinium-2-carboxamide,m.p. 174-6° C. [Elemental analysis:—C, 53.17; H, 4.14; N, 7.27%calculated:—C, 53.28; H, 4.21; N, 7.31%].

EXAMPLE 36 Compound GB

A solution of chlorotrimethylsilane (0.18 mL) in acetonitrile (6 mL) isadded dropwise to a stirred mixture of sodium iodide (648 mg), zinc dust(157 mg) andN-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-methoxy-1-oxidopyridinium-2-carboxamide(600 mg) in acetonitrile with cooling to 0-5° C. The mixture is stirredfor 3 hours at 0-5° C., diluted with diethyl ether, filtered andconcentrated to give a yellow solid. The solid is purified by flashchromatography (ethyl acetate/n-pentane 7:3 v/v as eluent on silica) togive a white solid (200 mg), m.p. 259-60° C. which is an iodine adduct.The solid is dissolved in ethyl acetate containing a few drops ofmethanol and the solution stirred with 10% aqueous sodium thiosulphate(1.5 mL). After 3 hours the organic phase is separated, dried (MgSO₄)and evaporated to giveN-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-methoxy-1-oxidopyridinium-2-carboxamidehemihydrate (100 mg), as a white solid, m.p. 204-5° C. [Elementalanalysis:—C, 49.95; H, 4.19; N, 10.10%. calculated:—C, 50.13; H, 4.46;N, 10.3%].

EXAMPLE 37 Compound GC-GE

A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (5 g) and2-chloroaniline (2.5 mL) in toluene (60 mL) is heated at reflux under aDean and Stark water trap for 3 hours. After concentration, the residueis dissolved in methanol (60 mL) and the stirred solution is treated at0° C. with sodium cyanoborohydride (2.1 g). The temperature is allowedto rise to room temperature, and the stirring is continued for 2 hours,before dilution with ethyl acetate (100 mL) and washing with saline (100mL). The organic layer is dried and concentrated, to give a brown oil.This oil is subjected to flash chromatography on silica gel, elutingwith a mixture of ethyl acetate and hexane (1:4 v/v), to giveN-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxybenzylamine (0.64 g), inthe form of an oil. [Elemental analysis: C, 69.5; H, 6.8; N, 4.1; Cl,10.6%. calculated: C, 68.8; H, 6.7; N, 3.2; Cl, 10.7%].

By proceeding in a similar manner, but using3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde instead of3-cyclopentyloxy-4-methoxybenzaldehyde, there is preparedN-(2-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzylamine.

By proceeding in a similar manner, but using4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde instead of3-cyclopentyloxy-4-methoxybenzaldehyde, there is preparedN-(2-chlorophenyl)-4-cyclopentyloxy-5-methoxy-2-aminomethylpyridine.

EXAMPLE 38 Compound GF-GJ

A stirred suspension of 2,6-dichlorobenzyltriphenylphosphonium bromide(2.5 g) in dry tetrahydrofuran (30 mL) is treated dropwise with asolution of potassium t-butoxide (0.56 g) in dry tetrahydrofuran (32 mL)at 0° C. After stirring at this temperature for 1 hour, it is treatedwith a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (1.1 g) in drytetrahydrofuran (15 mL). The reaction mixture is stirred from 0° C. to5° C. for 1.5 hours, and then allowed to warm to room temperature. Afterstirring overnight, the mixture is concentrated and the resultingresidue is treated with ethyl acetate (200 mL). The resulting organicsolution is filtered. The filtrate is concentrated and the resultingresidue is subjected to flash chromatography, eluting withdichloromethane, to givetrans-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)ethene(1.16 g), m.p. 47-49° C. [Elemental analysis: C, 66.4; H, 5.6; Cl,19.4%. calculated: C, 66.1; H, 5.55; Cl, 19.5%].

By proceeding in a similar manner, but using3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde instead of3-cyclopentyloxy-4-methoxybenzaldehyde, there is preparedtrans-2-(2,6-dichlorophenyl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxy)phenylethene.

By proceeding in a manner similar, but using3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde and2,6-difluorobenzyltriphenylphosphonium bromide, there is preparedtrans-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)-2-(2,6-difluorophenyl)ethene.

By proceeding in a similar manner, but using4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde instead of3-cyclopentyloxy-4-methoxybenzaldehyde, there is preparedtrans-2-(2,6-dichlorophenyl)-1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)ethene.

By proceeding in a manner similar, but using4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde and2,6-difluorobenzyltriphenyl-phosphonium bromide, there is preparedtrans-1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)-2-(2,6-difluorophenyl)ethene.

EXAMPLE 39 Compound GK-GM

Pyridinium dichromate (3.6 g) in dry dichloromethane (40 mL) undernitrogen is treated with(±)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol (2.0 g),in one portion. The resulting mixture is stirred for 1.5 hours, and thenfiltered through a pad of diatomaceous earth, and the pad is washed withdiethyl ether. The combined filtrate and ethereal washings are washedwith saturated aqueous cupric sulfate solution (2×30 mL), followed bywater (30 mL), and then dried over magnesium sulfate. The solvent isremoved under reduced pressure, and the resulting oily residue issubjected to flash chromatography on silica gel, eluting with ethylacetate, to give1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethane-1,2-dione (0.4g), in the form of a yellow solid, m.p. 117-119° C. [Elemental analysis:C, 70.1; H, 6.0; N, 4.1%. calculated: C, 70.1; H, 5.9; N, 4.3%].

By proceeding in a similar manner, but using(±)-1-(3-cyclopentyloxy-6-fluoro-4-methoxy)phenyl)-2-(pyrid-4-yl)ethanolinstead of(±)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol, there isprepared1-[(3-cyclopentyloxy-6-fluoro-4-methoxy)phenyl]-2-(pyrid-4-yl)ethane-1,2-dione.

By proceeding in a similar manner, but using(±)-1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)-2-(pyrid-4-yl)ethanolinstead of(±)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol, there isprepared1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)-2-(pyrid-4-yl)ethane-1,2-dione.

EXAMPLE 40 Compound GN

By proceeding in a similar manner as in Example 26, but replacing4-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid by the appropriatequantity of 5-cyclopentyl-6-methoxypyridazine-3-carboxylic acid chloridethere is prepared:

N-(3,5-dichloropyrid-4-yl)-5-cyclopentyloxy-6-methoxypyridazine-3-carboxamide.

EXAMPLE 41 Compound GO

Thionyl chloride (0.25 mL) is added to a stirred suspension of4-cyclopentyloxy-5-difluoromethoxypyridine-2-carboxylic acid (0.23 g) intoulene (5 mL) containing dry dimethylformamide (1 drop). The mixture isrefluxed for 1 hour under a nitrogen atmosphere, cooled and evaporatedto give the acid chloride which is dissolved in dimethylformamide (5mL).

Meanwhile sodium hydride (44 mg of a 60% dispersion in mineral oil) isadded to stirred solution of N-(3,5-dichloropyridin-4-yl)acetamide (172mg) in dimethylformamide (10 mL) and the mixture stirred for 1 hour. Themixture is then added to the solution of the acid chloride and thestirring continued for 1.5 hours at room temperature under a nitrogenatmosphere. Piperidine (0.23 mL) is added and the stirring continued fora further 1.5 hours. After evaporating the solvent, the residue, a brownoil, is purified by flash chromatography (n-pentane/ethyl acetate 7:3v/v as eluent on silica) to giveN-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-difluoromethoxypyridine-2-carboxamide,(0.14 g) as a white solid, m.p. 131-2° C. [Elemental analysis:—C, 48.85,H, 3.57; N, 9.91%. calculated:—C, 48.82; H, 3.62; N, 10.05%], [¹Hnmr inCDCl₃ with Me₄Si as standard:—1.71, 2H, m: 1.83, 2H, m; 1.93, 2H, m;2.03, 2H, m; 5.03, 1H, m; 6.64, 1H, t, J=74 Hz; 7.90, 1H, s; 8.37, 1H,s; 8.58, 2H, s: 9.88, 1H, br s.].

REFERENCE EXAMPLE 1

A mixture of 3,4-dimethoxy-6-fluorobenzaldehyde (3.7 g) and concentratedsulphuric acid (30 mL) is heated on a steam bath for 19 hours. Themixture is cooled, treated with ice-water (100 g) and stirred at 0° C.for 30 minutes. The mixture is extracted with chloroform (5×100 mL). Thecombined organic extracts are extracted with aqueous sodium hydroxidesolution (2×200 mL; 2 N). These aqueous extracts are acidified, bytreatment with concentrated hydrochloric acid, with cooling, and therust coloured solid formed is subjected to flash chromatography [using asolvent gradient of 3:1 to 2:1 v/v petroleum ether (b.p. 60-80° C.) andethyl acetate as eluent on a silica gel column], to give6-fluoro-3-hydroxy-4-methoxybenzaldehyde (1.67 g) in the form of a whitesolid, m.p. 153-154° C. [NMR (DMSO):—9.56 (s, 1H), 7.12 (d, 1H, J=8 Hz),7.01 (d, 1H, J=12 Hz), 3.88 (s, 3H)].

By proceeding in a similar manner, but using5,6-dimethoxypyridazine-3-carboxaldehyde instead of3,4-dimethoxy-6-fluorobenzaldehyde, there is prepared5-hydroxy-6-methoxypyridazine-3-carboxaldehyde.

REFERENCE EXAMPLE 2

A mixture of 6-fluoro-3-hydroxy-4-methoxybenzaldehyde (2 g), potassiumcarbonate (1.66 g) and anhydrous dimethylformamide (20 mL) is treatedwith cyclopentyl bromide (1.62 mL) and heated on a steam bath for 43hours. The mixture is cooled, poured into water (200 mL) and extractedwith diethyl ether (3×100 mL). The combined ethereal extracts are washedwith sodium hydroxide solution (2×50 mL; 2 N), and brine (2×50 mL),dried over magnesium sulphate and concentrated. The residual brown oilis subjected to flash chromatography [a solvent gradient of 9:1 to 4:1v/v petroleum ether (b.p. 60-80° C.) and ethyl acetate is used as eluenton a silica gel column] to give3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (1.42 g) in the form ofa yellow oil. [NMR (CDCl₃):—10.22 (s, 1H), 7.27 (d, 1H, J=8 Hz), 6.63(d, 1H, J=16 Hz), 4.81-4.76 (m, 1H), 3.91 (s, 3H), 2.01-1.57 (m, 8H)].

By proceeding in a similar manner but using the appropriate quantitiesof the appropriate alkyl halides there are prepared:—

2-Fluoro-5-isopropoxy-4-methoxybenzaldehyde, [NMR (CDCl₃):—10.21 (s,1H), 7.30 (d, 1H, J=8 Hz), 6.64 (d, 1H, J=12 Hz), 4.55 (m, 1H), 3.92 (s,3H), 1.36 (d, 6H, J=7 Hz)];

-   3-cyclohexyloxy-6-fluoro-4-methoxybenzaldehyde;-   3-butoxy-6-fluoro-4-methoxybenzaldehyde; and-   3-propoxy-6-fluoro-4-methoxybenzaldehyde.

By proceeding in a similar manner, but using the appropriate quantity of5-hydroxy-6-methoxypyridazine-3-carboxaldehyde instead of6-fluoro-3-hydroxy-4-methoxybenzaldehyde, there is prepared5-cyclopentyl-6-methoxypyridazine-3-carboxaldehyde.

REFERENCE EXAMPLE 3

A solution of 3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (1.4 g) inglacial acetic acid (20 mL) is treated with sulfamic acid (0.82 g) atroom temperature and stirred for 10 minutes. The resulting yellowsolution is cooled to 0° C. and treated with a solution of sodiumchlorite (0.69 g of an 80% pure sample) in water (20 mL) during 10minutes. The resulting yellow suspension is stirred at room temperaturefor 3 hours, poured into water (100 mL) and filtered to give3-cyclopentyloxy-6-fluoro-4-methoxybenzoic acid (0.88 g), in the form ofa white solid. [NMR (CDCl₃):—7.46 (d, 1H, J=8 Hz), 6.65 (d, 1H, J=12Hz), 4.80-0.76 (m, 1H), 3.90 (s, 3H), 2.01-1.58 (m, 8H)].

By proceeding in a similar manner but using the appropriate quantitiesof the appropriate benzaldehydes there are prepared:—

-   2-Fluoro-5-isopropoxy-4-methoxybenzoic acid;-   3-cyclohexyloxy-6-fluoro-4-methoxybenzoic acid;-   3-butoxy-6-fluoro-4-methoxybenzoic acid;-   3-propoxy-6-fluoro-4-methoxybenzoic acid; and-   5-cyclopentyl-6-methoxypyridazine-3-carboxylic acid.

REFERENCE EXAMPLE 4

A solution of 3-hydroxy-4-methoxybenzaldehyde (14.20 g) in drydimethylformamide (300 mL) is treated portionwise with sodium hydride(60% dispersion in oil; 3.70 g) at room temperature under nitrogen.3-Chlorocyclo-pentene (9.6 mL) is added and the resulting mixture isstirred overnight. The solvent is then removed under reduced pressureand the residue is partitioned between water (500 mL) anddichloromethane (500 mL) and the aqueous layer is further extracted withdichloromethane (500 mL). The combined organic extracts are dried andevaporated under reduced pressure and the residue is subjected to flashchromatography on silica gel, eluting with a mixture of ethyl acetateand pentane (1:1 v/v), to give3-cyclopent-2-enyloxy-4-methoxybenzaldehyde, in the form of a pale brownoil (11.2 g).

By proceeding in a similar manner, but using the appropriate quantity of6-fluoro-3-hydroxy-4-methoxybenzaldehyde, there is prepared3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzaldehyde.

REFERENCE EXAMPLE 5

A solution of 3-cyclopent-2-enyloxy-4-methoxybenzaldehyde (7.70 g) int-butanol (160 mL) and 2-methyl-2-butene (40 mL) is treated dropwisewith an aqueous solution (150 mL) containing sodium chlorite (80%technical grade; 4.39 g) and sodium dihydrogen phosphate (38.49 g), andleft to stand overnight. The resulting mixture is extracted withdichloromethane (2×250 mL), and the combined organic layers are driedover sodium sulfate, the solvent is removed under reduced pressure, andthe resulting residue is recrystallized from ethyl acetate, to give3-cyclopent-2-enyloxy-4-methoxybenzoic acid (5.89 g), in the form of acolorless solid. m.p. 160-163° C. [Elemental analysis: C, 66.4; H, 6.0%.calculated: C, 66.7; H, 6.0%].

By proceeding in a similar manner, but using the appropriate quantity of3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzaldehyde, there is prepared3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzoic acid.

REFERENCE EXAMPLE 6

A solution of 3-cyclopent-2-enyloxy-4-methoxybenzoic acid (5.89 g) indry dichloromethane (50 mL) under nitrogen at room temperature istreated with triethylamine (10.50 mL), followed by oxalyl chloride (2.40mL). The resulting mixture is stirred for 2.5 hours, then most of thesolvent is removed under reduced pressure, and the resulting residue istaken up in dry tetrahydrofuran (50 mL) and filtered through a pad ofdiatomaceous earth. The resulting solution, containing3-cyclopent-2-enyloxy-4-methoxybenzoyl chloride, is used immediatelywithout further purification.

By proceeding in a similar manner, but using the appropriate quantity of3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzoic acid, there is prepared

-   3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzoyl chloride.

REFERENCE EXAMPLE 7

A stirred suspension of sodium hydride (60% in oil, 0.88 g) in drydimethylformamide (44 mL) under nitrogen at between 5-10° C. is treatedwith a solution of 3-hydroxy-4-methoxy benzaldehyde (3.35 g) in drydimethylformamide (6.3 mL). The resulting mixture is allowed to warm toroom temperature and stirred for 40 minutes before recooling to between5-10° C. A solution of 4-(p-toluenesulfonoxy)cyclopentene (5.24 g) indry dimethylformamide (12.6 mL) is added dropwise maintaining thetemperature below 10° C. The resulting mixture is allowed to warm toroom temperature, left to stand for 46 hours, and then poured into 5%aqueous potassium carbonate (305 mL). t-Butyl methyl ether is added (150mL), and the layers are thoroughly stirred and separated. The aqueouslayer is further extracted with t-butyl methyl ether (2×75 mL), thecombined organic extracts are washed with water (3×30 mL) and dried overmagnesium sulfate. The solvent is removed under reduced pressure and theresulting residue is subjected to flash chromatography on silica gel,eluting with mixtures of ethyl acetate and pentane (1:10 to 3:10), togive 3-cyclopent-3-enyloxy-4-methoxybenzaldehyde as a pale amber viscousoil that slowly crystallizes on standing (1.75 g). Recrystallization ofa portion (0.5 g) from cyclohexane gives an analytically pure sample(0.4 g), m.p. 60-62° C. [Elemental analysis: C, 71.8; H, 6.5%.calculated: C, 71.5; H, 6.8%].

By proceeding in a similar manner, but using the appropriate quantity of6-fluoro-3-hydroxy-4-methoxybenzaldehyde, there is prepared3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzaldehyde.

REFERENCE EXAMPLE 8

A stirred solution of 3-cyclopent-3-enyloxy-4-methoxybenzaldehyde (1.75g) in t-butanol (36.5 mL) and 2-methyl-2-butene (9.0 mL) is treateddropwise with an aqueous solution (34 mL) containing sodium chlorite(80% technical grade; 1.0 g) and sodium dihydrogen phosphate (8.75 g).The resulting mixture is further stirred for 5 hours, the layers areseparated and the aqueous layer is extracted with t-butyl methyl ether(3×30 mL). The combined organic layers are washed with water (2×15 mL),dried over sodium sulfate and the solvent removed under reducedpressure. The resulting residue is recrystallized from ethyl acetate togive 3-cyclopent-3-enyloxy-4-methoxybenzoic acid (1.31 g), in the formof a colorless solid, m.p. 171-173° C. [Elemental analysis: C, 66.6; H,6.0%. calculated: C, 66.7; H, 6.0%].

By proceeding in a similar manner, but using the appropriate quantity of3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzaldehyde, there is prepared3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzoic acid.

REFERENCE EXAMPLE 9

A solution of 3-cyclopent-3-enyloxy-4-methoxybenzoic acid (1.33 g) indry tetrahydrofuran (20 mL) under nitrogen at room temperature istreated with triethylamine (2.36 mL), followed by oxalyl chloride (0.70mL). The resulting mixture is stirred for 1 hour and then filteredthrough a pad of diatomaceous earth. The solid collected is washed withdry tetrahydrofuran (10 mL). The resulting combined filtrates,containing 3-cyclopent-3-enyloxy-4-methoxybenzoyl chloride, is usedimmediately without further purification.

By proceeding in a similar manner, but using the appropriate quantity of3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzoic acid, there is prepared3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzoyl chloride.

REFERENCE EXAMPLE 10

A mixture of 2-fluoro-5-hydroxy-4-methoxybenzaldehyde (3 g),endonorborneol (1.33 g) and triphenylphosphine (4.62 g) are dissolved indry tetrahydrofuran (3.5 mL) and treated withdiisopropylazodicarboxylate (3.6 g). The mixture is heated with stirringat reflux for 24 hours, cooled and treated with water (75 mL). Themixture is extracted with dichloromethane (3×100 mL) and the combinedorganic extracts washed with 2 N sodium hydroxide (2×75 mL), brine (75mL), dried (magnesium sulfate) and concentrated to give3-exonorbornyloxy-6-fluoro-4-methoxybenzaldehyde as a brown oil (2.1 g).[NMR (CDCl₃):— 10.24 (s, 1H), 7.23 (d, 1H, J=7 Hz), 6.64 (d, 1H, J=12Hz), 4.22 (d, 1H, J=8 Hz), 3.92 (s, 3H), 2.5 (d, 1H, J=5 Hz), 2.33 (bs,1H), 1.86-1.1 (m, 10H)].

REFERENCE EXAMPLE 11

To a solution of diisopropylamine (0.16 g) in tetrahydrofuran (2 mL) at−78° C. is added a 2.5 N solution of n-butyl lithium in hexanes (0.62mL). The solution is allowed to warm to −10° C. and cooled back to −78°C. A solution of 3,5-dichloro-4-methylpyridine (0.25 g) in drytetrahydrofuran (4 mL) is added, stirred for 0.5 hours at −60° C. andtreated with 3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (0.25 g) indry tetrahydrofuran (4 mL). The reaction mixture is allowed to warm toroom temperature over 1 hour and stirred overnight. The mixture istreated with 2N ammonium chloride (50 mL) and extracted with ethylacetate (3×50 mL). The combined organic extracts are washed with brine(50 mL), dried (magnesium sulfate) and evaporated to give2-(3,5-dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanol(0.22 g). [NMR (CDCl₃):— 8.44 (s, 2H), 6.97 (d, 1H, J=7 Hz), 6.56 (d,1H, J=12 Hz), 5.34 (m, 1H), 4.74 (m, 1H), 3.83 (s, 3H), 3.5 (dd, 1H, J=8Hz, 8 Hz), 3.32 (dd, 1H, J=5 Hz, 6 Hz), 2.07 (d, 1H, J=6 Hz), 1.93-1.55(m, 8H)].

REFERENCE EXAMPLE 12

A mixture of 2-fluoro-5-isopropoxy-4-methoxybenzoic acid (7.2 g) andlithium iodide (24 g) in collidine (120 mL) is heated at 150° C.overnight, cooled and dissolved in 2 N sodium hydroxide (200 mL) andwashed with ethyl acetate (3×150 mL). The aqueous solution is acidifiedto pH 1 with concentrated hydrochloric acid and extracted with ethylacetate (3×100 mL). The combined organic layers are dried (magnesiumsulfate) and concentrated to give an oil. The oil is subjected to mplcon silica gel using petroleum ether: ethyl acetate (2:1 v/v) as eluentto give 2-fluoro-4-hydroxy-5-isopropylbenzoic acid (5.7 g). [NMR(DMSO):— 7.32 (d, 1H, J=8 Hz), 6.67 (d, 1H, J=12 Hz), 4.47 (m, 1H), 1.24(d, 6H, J=6 Hz)].

By proceeding in a similar manner, but using the appropriate quantitiesof the appropriate acid, is prepared3-cyclopentyloxy-6-fluoro-4-hydroxybenzoic acid, [NMR (CDCl₃):— 7.44 (d,1H, J=8 Hz), 6.73 (d, 1H, J=12 Hz), 4.86 (m, 1H), 2.05-1.63 (m, 8H)].

REFERENCE EXAMPLE 13

2-Fluoro-4-hydroxy-5-isopropyloxybenzoic acid (5.7 g) is dissolved inmethanol (200 mL) and concentrated sulfuric acid (1 mL) and heated at70° C. for 5 hours. The solution is concentrated and the resultant oilsubjected to mplc on silica gel using petroleum ether: ethyl acetate(4:1 v/v) as eluent to givemethyl-2-fluoro-4-hydroxy-5-isopropyloxybenzoate (5.7 g). [NMR (CDCl₃)7.38 (d, 1H, J=7 Hz), 6.67 (d, 1H, J=12 Hz), 4.85 (m, 1H), 3.9 (s, 3H),1.3 (d, 6H, J=7 Hz)].

By proceeding in a similar manner, but using the appropriate quantitiesof the appropriate acid, is prepared:—

Methyl-3-cyclopentyloxy-4-hydroxy-6-fluorobenzoate, [NMR (CDCl₃):— 7.38(d, 1H, J=6 Hz), 6.68 (d, 1H, J=12 Hz), 4.87 (m, 1H), 3.91 (s, 3H),2.03-1.62 (m, 8H)].

REFERENCE EXAMPLE 14

Methyl-2-fluoro-4-hydroxy-5-isopropyloxybenzoate (5.7 g) is dissolved indimethylformamide (150 mL) and treated with potassium carbonate (5.1 g)and potassium iodide (2 g). Chlorodifluoromethane is slowly bubbledthrough the stirred solution which is slowly heated to 70° C. After 7hours the reaction is terminated by cooling and quenching with water(100 mL). The solution is extracted with ethyl acetate (4×100 mL) andthe combined organic extracts washed with brine (200 mL) and dried(magnesium sulfate). The organic solution is evaporated to give an oil,which is subjected to mplc on silica gel using petroleum ether: ethylacetate (9:1 v/v) as eluent to givemethyl-4-difluoromethoxy-2-fluoro-5-isopropyloxybenzoic acid (5.8 g).[NMR (CDCl₃):— 7.52 (d, 1H, J=8 Hz), 6.97 (d, 1H, J=12 Hz), 6.67 (t, 1H,J=72 Hz), 4.56 (m, 1H), 3.93 (s, 3H), 1.36 (d, 6H, J=6 Hz)].

By proceeding in a similar manner, but using the appropriate quantity ofthe appropriate ester is prepared: -

Methyl-3-cyclopentyloxy-4-difluoromethoxy-6-fluorobenzoate. [NMR(CDCl₃):— 7.50 (d, 1H, J=7 Hz), 6.97 (d, 1H, J=12 Hz), 6.65 (t, 1H, J=72Hz), 4.83 (m, 1H), 3.94 (s, 3H), 1.98-1.62 (m, 8H)].

REFERENCE EXAMPLE 15

Methyl-2-fluoro-4-difluoromethoxy-5-isopropyloxybenzoate (5.8 g) isdissolved in methanol (100 mL) and water (30 mL) with potassiumcarbonate (3.9 g) and stirred at 70° C. for 4 hours. After concentrationthe residue is dissolved in water (150 mL) and washed with ether (150mL). The aqueous solution is acidified with 2 M hydrochloric acid andthe precipitate collected as2-fluoro-4-difluoromethoxy-5-isopropyloxybenzoic acid (5.2 g). [NMR(CDCl₃):— 7.60 (d, 1H, J=7 Hz), 7.02 (d, 1H, J=12 Hz), 6.70 (t, 1H, J=72Hz), 4.57 (m, 1H), 1.38 (d, 6H, J=7 Hz)].

By proceeding in a similar manner, but using the appropriate quantitiesof the appropriate ester is prepared3-cyclopentyloxy-4-difluoromethoxy-6-fluorobenzoic acid. [NMR (CDCl₃):—7.57 (d, 1H, J=8 Hz), 7.02 (d, 1H, J=12 Hz), 6.68 (t, 1H, J=72 Hz), 4.84(m, 1H), 2.0-1.6 (m, 8H)].

REFERENCE EXAMPLE 16

A stirred solution of diisopropylamine (14 mL) in dry tetrahydrofuran(150 mL), is treated dropwise with a solution of butyl lithium inhexanes (40 mL; 2.5 M), under nitrogen, while keeping the temperature atbelow −70° C. The resulting mixture is then stirred for a further periodof 30 minutes at below −70° C. The stirred mixture, while it is stillmaintained at below −70° C., is then treated dropwise with a solution of4-picoline (9.3 g) in dry tetrahydrofuran (20 mL). The stirred mixtureis maintained at below −70° C. for a further 45 minutes. The stirredmixture, while it is still maintained at below −70° C., is then treatedwith a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (22.0 g) indry tetrahydrofuran (100 mL), and it is stirred at below −70° C. for afurther 30 minutes. The resulting mixture is then allowed to warm toroom temperature overnight, and then treated with saturated aqueousammonium chloride solution (200 mL). The layers are separated and theaqueous layer is further extracted with ethyl acetate (3×300 mL). Thecombined organic extracts are dried over magnesium sulfate andevaporated to dryness. The resulting residue is recrystallized fromethyl acetate, to give(±)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol (28.5 g),in the form of a cream solid, m.p. 102-103° C.

By proceeding in a similar manner using3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (that is prepared as inReference Example 2) instead of 3-cyclopentyloxy-4-methoxybenzaldehyde,there is prepared(±)-1-(3-cyclopentyloxy-6-fluoro-4-methoxy)phenyl)-2-(pyrid-4-yl)ethanol.

REFERENCE EXAMPLE 17

Sodium methoxide in methanol (82.65 mL of a 1 M solution) is addedslowly to a stirred solution of methyl 6-chloro-5-nitronicotinate (17 g)in anhydrous methanol (250 mL) and the mixture stirred for 8 hours. Themixture is concentrated, the residue treated with water and thenextracted into ethyl acetate. The extracts are washed with water,treated with decolourising charcoal and dried (MgSO₄). Concentrationafforded methyl 6-methoxy-5-nitronicotinate (9.8 g) as an orange solid.Recrystallisation from cyclohexane afforded white needles, m.p. 118-9°C.

REFERENCE EXAMPLE 18

A solution of methyl 6-methoxy-5-nitronicotinate (5.4 g) in ethylacetate (120 mL) is hydrogenated using 5% palladium on carbon (1 g) ascatalyst. When hydrogen uptake ceased the mixture is filtered through apad of diatomaceous earth and the filtrate evaporated. The residue istriturated with n-pentane and methyl t-butyl ether to give methyl5-amino-6-methoxynicotinoate (4.3 g) as a light-brown solid, m.p. 108-9°C. [Elemental analysis: —C, 52.99; H, 5.49; N, 15.25%. calculated: —C,52.74; H, 5.53; N, 15.38%.]

REFERENCE EXAMPLE 19

Concentrated hydrochloric acid (9.06 mL of strength 36%) is added to astirred suspension of methyl 5-amino-6-methoxynicotinoate (3.3 g) inwater (20 mL). The mixture is cooled to 0° C. and treated dropwise witha solution of sodium nitrite (1.37 g) in water (5 mL). After 30 minutesat 0° C. a solution of sodium tetrafluoroborate (2.84 g) in water (10mL) is added. After a further 30 minutes the precipitated diazonium saltis collected, washed with a little ice-cold water then with diethylether and sucked dry. Potassium carbonate (1.0 g) is added totrifluoroacetic acid (32 mL) at 0° C. followed by the addition of thediazonium salt in one portion. The mixture is stirred at reflux for 18hours, cooled then poured into iced water and stirred for 1 hour. Theaqueous mixture is neutralised with solid sodium bicarbonate andextracted with ethyl acetate. The extracts are washed with water anddried (MgSO₄). Concentration afforded methyl5-hydroxy-6-methoxynicotinoate (2.86 g) as a beige solid. This materialis used without further purification.

REFERENCE EXAMPLE 20

A mixture of methyl 5-hydroxy-6-methoxynicotinoate (250 mg), anhydrouspotassium carbonate (600 mg) and cyclopentyl bromide (0.26 mL) in drydimethylformamide (5 mL) is stirred and heated at 60±5° C. for 24 hours.The mixture is cooled to room temperature, diluted with water andextracted with ethyl acetate. The extracts are washed with water anddried (MgSO₄). Concentration gave methyl5-cyclopentyloxy-6-methoxynicotinoate (290 mg) as an oil.

REFERENCE EXAMPLE 21

A solution of potassium hydroxide (168 mg) in water (1 mL) is added to asolution of methyl 5-cyclopentyloxy-6-methoxynicotinoate (250 mg) inmethanol (3 mL) and the mixture stirred for 4 hours then allowed tostand at room temperature overnight. The mixture is concentrated, theresidue dissolved in water and the mixture adjusted to pH 6 by theaddition of concentrated hydrochloric acid. The mixture is extractedwith ethyl acetate, the extracts dried (MgSO₄) and concentrated to givea cream solid. The solid is dried at 100° C. to give5-cyclopentyloxy-6-methoxynicotinic acid (140 mg), m.p. 191-2° C.[Elemental analysis: —C, 60.7; H, 6.43; N, 5.78%. calculated: —C, 60.75;H, 6.37; N, 5.90%.].

REFERENCE EXAMPLE 22

6-Chloro-5-methoxypyridine-2-carbonyl chloride (5.8 g) is added to drycyclopentanol (50 mL) and the mixture refluxed for 4 hours. The mixtureis concentrated, the residue dissolved in ethyl acetate (400 mL) and theethyl acetate solution is washed with water (3×250 mL). After drying(MgSO₄) the solution is evaporated to dryness to give cyclopentyl6-chloro-5-methoxypyridine-2-carboxylate (6.3 g) as a buff solid, m.p.90-92° C. [Elemental analysis: —C, 55.9; H, 5.47; Cl, 13.9; N, 5.48%.calculated: —C, 56.36; H, 5.52; Cl, 13.8; N, 5.48%.].

REFERENCE EXAMPLE 23

Sodium hydride (887 mg of a 60% dispersion in oil) is added to asolution of cyclopentanol (3.35 mL) in dry tetrahydrofuran (127 mL) andthe mixture stirred for 1.5 hours. Cyclopentyl6-chloro-5-methoxypyridine-2-carboxylate (6.3 g) is added and themixture is stirred at room temperature for 21 hours. The mixture ispoured into saturated aqueous ammonium chloride (500 mL) and theresulting mixture extracted with ethyl acetate (2×500 mL). The combinedextracts are washed with saturated aqueous sodium bicarbonate (500 mL)and water (500 mL). After drying (MgSO₄) the solution is evaporated todryness to give a yellow oil which is purified by flash chromatography(silica with pentane/ethyl acetate 9:1 v/v as eluent) affordingcyclopentyl 6-cyclopentyloxy-5-methoxypyridine-2-carboxylate (3.6 g) asan oil.

REFERENCE EXAMPLE 24

Potassium hydroxide (1.98 g) in water (12 mL) is added to a solution ofcyclopentyl 6-cyclopentyloxy-5-methoxypyridine-2-carboxylate (3.6 g) inmethanol (35 mL) and the mixture stirred at room temperature for 2.5hours. The solution is concentrated to half of the original volume anddiluted with water. The solution is acidified to pH 4 with concentratedhydrochloric acid and the product extracted with ethyl acetate. Theextracts are dried (MgSO₄) and concentrated to give6-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (1.38 g) as ayellow solid, m.p. 96-99° C.

REFERENCE EXAMPLE 25

Sodium thiomethoxide (9.1 g) in dry methanol (50 mL) is added dropwiseto a stirred solution of methyl 6-chloro-5-nitronicotinoate (25.1 g) indry methanol (400 mL) and the mixture stirred for 4 hours. The pastymixture is evaporated to low volume, diluted with water and the productextracted into ethyl acetate. The extracts are washed with water andbrine, and finally dried (MgSO₄). Evaporation gave methyl6-methylthio-5-nitronicotinoate (16.8 g) as a yellow solid. The solidcan be recrystallised from cyclohexane to give a yellow solid m.p.115-6° C.

REFERENCE EXAMPLE 26

Iron powder (22.4 g) is added portionwise to a solution of methyl6-methylthio-5-nitronicotinoate (16.8 g) in a mixture of glacial aceticacid (175 mL) and water (30 mL) whilst heating at 95±5° C. After theaddition is complete the mixture is heated for a further 1.5 hours. Thecooled mixture is diluted with water and extracted with ethyl acetate.The extracts are dried (MgSO₄), treated with decolourising charcoal andevaporated to give methyl 5-amino-6-methylthionicotinoate as a darkyellow solid (12.5 g).

REFERENCE EXAMPLE 27

Concentrated hydrochloric acid (31.2 mL) is added to a stirredsuspension of methyl 5-amino-6-methylthionicotinoate (12.5 g) in water(70 mL). The stirred mixture is cooled to 0-5° C. and treated dropwisewith a solution of sodium nitrite (4.75 g) in water (35 mL), thenstirred for a further 30 minutes at 0-5° C. A solution of sodiumtetrafluoroborate (9.84 g) in water (35 mL) is added and the mixturestirred for 1 hours. The water is removed in vacuo, the solid residuetriturated with diethyl ether, collected and pumped dry. The solid isadded portionwise to a mixture of anhydrous potassium carbonate (3.5 g)and trifluoroacetic acid (100 mL) and the resulting mixture stirred atroom temperature for 72 hours. The mixture is evaporated to low volume,diluted with water and the product extracted into ethyl acetate. Theextracts are washed with water, dried (MgSO₄) and evaporated to afford adark oil. The oil is triturated with n-pentane then methyl t.butyl etherto give methyl 5-hydroxy-6-methylthionicotinoate (8.9 g) as a lightbrown solid, mp. 152-3° C.

REFERENCE EXAMPLE 28

Cyclopentyl bromide (0.78 mL) is added to a stirred mixture of methyl5-hydroxy-6-methylthionicotinoate (810 mg) and anhydrous potassiumcarbonate (1.8 g) in dry dimethylformamide (15 mL). The mixture isheated at 60±5° C. for 8 hours. After cooling the mixture isconcentrated in vacuo and the residue partitioned between water andethyl acetate. The ethyl acetate phase is isolated, washed with waterand dried (MgSO₄). The solvent is removed in vacuo to give methyl5-cyclopentyloxy-6-methylthionicotinoate (920 mg) as a light brown oil.[Elemental analysis: —C, 58.41; H, 6.41; N, 5.24%. calculated: —C, 58.2;H, 6.44; N, 5.33%.].

REFERENCE EXAMPLE 29

A solution of potassium hydroxide (582 mg) in water (6 mL) is added to astirred solution of methyl 5-cyclopentyloxy-6-methylthionicotinoate (920mg) in methanol at room temperature and the mixture stirred for 6 hours.After concentrating in vacuo the mixture is diluted with water andacidified to pH 1 with aqueous 2 M hydrochloric acid. The product isextracted into ethyl acetate, the extracts treated with decolourisingcharcoal, dried (MgSO₄) and evaporated. The residue is triturated withn-pentane to give 5-cyclopentyloxy-6-methylthionicotinic acid (640 mg)as a white solid, m.p. 177-8° C. [Elemental analysis: —C, 56.90; H,6.02; N, 5.52%. calculated: —C, 56.90; H, 5.97; N, 5.53%.].

REFERENCE EXAMPLE 30

A mixture of methyl 5-hydroxy-6-methylthionicotinoate (3 g), isopropylbromide (2.1 mL) and anhydrous potassium carbonate (3 g) in drydimethylformamide (35 mL) is stirred and heated at 60±5° C. for 18hours. After cooling the solvent is removed in vacuo and the residuepartitioned between ethyl acetate and water. The organic phase is washedwith brine and dried (MgSO₄). Evaporation gives a brown oil which ispurified by flash chromatography (pentane/ethyl acetate 4:1 v/v aseluent on silica) to give methyl 5-isopropyloxy-6-methylthionicotinoate(2.36 g) as a pale yellow oil. [Elemental analysis: —C, 54.40; H, 6.24;N, 5.88%. calculated: —C, 54.75; H, 6.27; N, 5.81%.].

REFERENCE EXAMPLE 31

Potassium hydroxide (770 mg) in water (8 mL) is added to a solution ofmethyl 5-isopropyloxy-6-methylthionicotinoate (1.1 g) in methanol (15mL) and the mixture stirred at room temperature for 6 hours. Afterconcentrating in vacuo the residue is dissolved in water and acidifiedto pH 1 with concentrated aqueous hydrochloric acid. The mixture isextracted with ethyl acetate, the extracts washed with water and dried(MgSO₄). The solvent is removed in vacuo to give5-isopropyloxy-6-methylthionicotinic acid as a white solid, m.p. 154-5°C.

REFERENCE EXAMPLE 32

Trityl chloride (9.43 g) is added in one portion to a solution of2-hydroxymethyl-5-methoxy-4-pyridone (5 g) and 4-dimethylaminopyridine(4.2 g) in dry dimethylformamide (80 mL) and the solution stirred atroom temperature for 12 hours. The mixture is then heated on a steambath for 3 hours and diluted with iced water (300 mL) to give a lightbrown solid. The solid is collected, washed with water and sucked dry.The solid is dissolved in hot ethyl acetate to give a clear solutionwhich immediately deposits a granular off-white solid. The solid doesnot redissolve on further heating. After cooling the solid is collected,washed with ethyl acetate and diethyl ether and dried to give5-methoxy-2-trityloxymethyl-4-pyridone (7.5 g) as an off-white solid,m.p. 185-7° C.

REFERENCE EXAMPLE 33

Diisopropyl azodicarboxylate (1.47 mL) is added to a solution oftriphenylphosphine (1.96 g) in dry tetrahydrofuran (20 mL) with coolingto 0-5° C. under a nitrogen atmosphere. The pasty mixture is stirred fora further 30 minutes and then a solution of5-methoxy-2-trityloxymethyl-4-pyridone (2.0 g) in dry tetrahydrofuran(25 mL) is added followed by the addition of cyclopentanol (0.68 mL).The mixture is stirred at reflux for 8 hours, cooled and the solventremoved in vacuo. The residue is diluted with water and extracted withethyl acetate. The extracts are dried (MgSO₄) and evaporated to give abrown oil. The oil is purified by flash chromatography (n-pentane/ethylacetate 9:1 v/v as eluent on neutral alumina) to give4-cyclopentyloxy-5-methoxy-2-trityloxypyridine (1.24 g) as a whitesolid, m.p. 132-3° C. [Elemental analysis: —C, 80.00; H, 6.70; N, 2.70%.calculated: —C, 79.97; H, 6.71; N, 3.00%.].

REFERENCE EXAMPLE 34

90% Formic acid (5.5 mL) is added to a suspension of4-cyclopentyloxy-5-methoxy-2-trityloxypyridine (1.2 g) in ethyl acetate(8.5 mL) and the mixture stirred at room temperature for 1 hours. Themixture is diluted with ethyl acetate and washed with brine then aqueoussodium bicarbonate until the washings are neutral. The brine washingsare neutralised with solid sodium bicarbonate and extracted with ethylacetate. After drying (MgSO₄) the extracts are evaporated to give4-cyclopentyloxy-2-hydroxymethyl-5-methoxypyridine (360 mg) as a whitesolid, m.p. 93-94.5° C. [Elemental analysis: —C, 64.7; H, 7.80; N,6.11%. calculated: —C, 64.55; H, 7.68; N, 6.27%.].

REFERENCE EXAMPLE 35

Solid potassium permanganate (5.87 g) is added portionwise during 30minutes to a suspension of4-cyclopentyloxy-2-hydroxymethyl-5-methoxypyridine (4.0 g) in water (100mL) at 50±5° C. When the addition is complete the mixture is heated at70±5° C. for 45 min and then cooled to room temperature. A solution ofpotassium hydroxide (1.95 g) in water (50 mL) is added followed bysufficient isopropanol to react with excess potassium permanganate.After stirring for 10 minutes the mixture is filtered throughdiatomaceous earth and the filtrate concentrated to ˜70 mL. The solutionis acidified to pH 2 with concentrated aqueous hydrochloric acid andextracted with chloroform. After drying (MgSO₄) the extracts areevaporated to give 4-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid(2.5 g) as a white solid, m.p. 184-5° C. [¹Hnmr in D₆-DMSO shiftsrelative to Me₄Si:— 1.55-1.79, 6H, m; 1.95, 2H, m; 3.92, 3H, s; 5.00,1H, m; 7.59, 1H, s; 8.24, 1H, s.].

REFERENCE EXAMPLE 36

Hydrogen chloride gas is passed into a suspension of5-methoxy-4-pyridone-2-carboxylic acid (60.89 g) in methanol (800 mL)with ice bath cooling to 0-5° C. After 2 hours the passage of hydrogenchloride is stopped and then the mixture is refluxed gently for 5 hours.After cooling the solution is allowed to stand overnight. Theprecipitate is collected, and the filtrate evaporated to dryness. Thecollected solid and the residue are combined, dissolved in the minimumamount of water and then basefied to pH 8 with sodium bicarbonate. Thesolution is extracted with n-butanol and the extracts evaporated invacuo to give methyl 5-methoxy-4-pyridone-2-carboxylate (38.3 g) as apale yellow solid, m.p 185-6° C.

REFERENCE EXAMPLE 37

Diisopropyl diazodicarboxylate (6.13 mL) is added to a solution oftriphenylphosphine (8.16 g), methyl 5-methoxy-4-pyridone-2-carboxylate(3.8 g) and cyclopentanol (2.82 mL) in dry tetrahydrofuran (200 mL) withcooling to 10-15° C. under a nitrogen atmosphere. The mixture is stirredat room temperature for 30 minutes then at reflux for 48 hours. Afterconcentrating, the residue is diluted with water and extracted withethyl acetate and the extracts washed with water, dried (MgSO₄) andevaporated to give a yellow oil. The oil is purified by flashchromatography (pentane/ethyl acetate 3:2 v/v as eluent on silica) togive methyl 4-cyclopentyloxy-5-methoxypyridine-2-carboxylate (4.1 g) asa golden oil.

By proceeding in a similar manner, but replacing cyclopentanol with theappropriate quantity of (±)-tetrahydrothiophen-3-ol, there isprepared:—(±)-methyl5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxylate as asolid. [¹Hnmr in D₆-DMSO shifts relative to Me₄Si:— 2.04, 1H, m; 2.32,1H, m; 2.91, 3H, m; 3.20, 1H, dd; 3.85, 3H, s; 3.94, 3H, s; 5.44, 1H m;7.68, 1H, s; 8.31, 1H, s.].

By proceeding in a similar manner, but replacing cyclopentanol with theappropriate quantity of cyclopropylmethanol, there is prepared:—

methyl 4-cyclopropylmethoxy-5-methoxypyridine-2-carboxylate as a whitesolid, m.p. 93-4° C.

By proceeding in a similar manner, but replacing cyclopentanol with theappropriate quantity of isopropanol, there is prepared:—

A 2:1 mixture of ethyl 4-isopropyloxy-5-methoxypyridine-2-carboxylateand methyl 4-isopropyloxy-5-methoxypyridine-2-carboxylate as an oil.

By proceeding in a similar manner, but replacing cyclopentanol with theappropriate quantity of (±)-tricyclo[2.2.1.0.^(2.6).]heptan-2-ol, thereis prepared:—

A 1:1 mixture of (±)-ethyl5-methoxy-4-(tricyclo[2.2.1.0.^(2.6).]hept-2-yloxy)pyridine-2-carboxylateand (±)-methyl5-methoxy-4-(tricyclo[2.2.1.0.^(2.6).]hept-2-yloxy)pyridine-2-carboxylate.

REFERENCE EXAMPLE 38

A solution of potassium hydroxide (4.71 g) in water (32 mL) is added toa solution of methyl 4-cyclopentyloxy-5-methoxypyridine-2-carboxylate(7.03 g) in methanol (188 mL) and the mixture allowed to stand for 45hours. After concentrating in vacuo the residue is dissolved in water,washed with ethyl acetate and basefied to pH 5 with concentrated aqueoushydrochloric acid. The mixture is extracted with dichloromethane, theextracts dried (MgSO₄) and evaporated to give4-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (2.4 g) as a whitesolid.

By proceeding in a similar manner, but replacing methyl4-cyclopentyloxy-5-methoxypyridine-2-carboxylate with the appropriatequantity of (±)-methyl5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxylate, there isprepared:—

(±)-5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxylic acid,as a white solid, m.p. 190-1° C. [Elemental analysis: —C, 51.3; H, 5.17;N, 5.53%. calculated: —C, 57.7; H, 5.13; N, 5.49%.]

By proceeding in a similar manner, but replacing methyl4-cyclopentyloxy-5-methoxypyridine-2-carboxylate with the appropriatequantity of methyl 4-cyclopropylmethoxy-5-methoxypyridine-2-carboxylatethere is prepared:—

4-cyclopropylmethoxy-5-methoxypyridine-2-carboxylic acid as a whitesolid, m.p. 146-7° C. [¹Hnmr in D₆-DMSO shifts relative to Me₄Si:— 0.37,2H, m; 0.60, 2H, m; 1.24, 1H, m; 3.94, 3H, s; 3.98, 2H, d; 7.58, 1H, s;8.25, 1H, s.].

By proceeding in a similar manner, but replacing methyl4-cyclopentyloxy-5-methoxypyridine-2-carboxylate with the appropriatequantity of a 2:1 mixture of ethyl4-isopropyloxy-5-methoxypyridine-2-carboxylate and methyl4-isopropyloxy-5-methoxypyridine-2-carboxylate, there is prepared:—

4-isopropyloxy-5-methoxypyridine-2-carboxylic acid, m.p. 172-3° C.[Elemental analysis: —C, 56.77; H, 6.21; N, 6.74%. calculated: —C,56.87; H, 6.20; N, 6.63%.]

By proceeding in a similar manner, but replacing methyl4-cyclopentyloxy-5-methoxypyridine-2-carboxylate with the appropriatequantity of a 1:1 mixture of (±)-ethyl5-methoxy-4-(tricyclo[2.2.1.0.^(2.6).]hept-2-yloxy)pyridine-2-carboxylateand (±)-methyl5-methoxy-4-(tricyclo[2.2.1.0.^(2.6).]hept-2-yloxy)pyridine-2-carboxylate,there is prepared:—

(±)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6).]hept-2-yloxy)pyridine-2-carboxylicacid, as a white solid m.p. 188-9° C. [¹Hnmr in D₆-DMSO shifts relativeto Me₄Si:— 1.28, 2H, br.d; 1.36, 3H, br.s; 1.59, 1H, d; 1.78, 1H, d;1.13, 1H, br.s; 2.94, 3H, s; 4.58, 1H, br.s; 7.66, 1H, s; 8.24, 1H, s.].

REFERENCE EXAMPLE 39

Manganese dioxide (6.0 g) is added to a solution of4-cyclopentyloxy-2-hydroxymethyl-5-methoxypyridine (2.0 g) in diethylether (80 mL) and dichloromethane (10 mL) and the mixture stirred atroom temperature for 90 hours. After filtering the filter pad is washedwith dichloromethane and the combined filtrate and washings areevaporated to give a white solid. The solid is dried under high vacuumto give 4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde (1.65 g).[¹Hnmr in D₆-DMSO shifts relative to Me₄Si:— 1.55-1.79, 6H, m; 1.97, 2H,m; 3.96, 3H, s; 5.03, 1H, m; 7.45, 1H, s; 8.41, 1H, s; 9.83, 1H, s.].

REFERENCE EXAMPLE 40

n-Butyllithium (3.21 mL of 2.5 M solution) is added to a solution ofdiisopropylamine (1.15 mL) in dry tetrahydrofuran (25 mL) with thetemperature being maintained below −60° C. After 30 min a solution of3,5-dichloro-4-methylpyridine (1.21 g) in tetrahydrofuran (7 mL) isadded dropwise and the mixture stirred for a further 30 min. A solutionof 4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde (1.65 g) intetrahydrofuran (7 mL) is added and the mixture stirred for 4 hourswhilst being allowed to warm to room temperature. After a further 18hours at room temperature the mixture is diluted with saturated aqueousammonium chloride (50 mL) and extracted with ethyl acetate. The extractsare washed with water, dried (MgSO₄) and evaporated to give a yellowoil. The oil is triturated with n-pentane to give(±)-1-(4-cyclopentyloxy-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanol(1.4 g) as an off-white solid, m.p. 110-112° C. [¹Hnmr in D₆-DMSO shiftsrelative to Me₄Si:— 1.55-1.78, 6H, m; 1.95, 2H, m; 3.27, 2H, m; 3.79,3H, s; 4.89, 2H, m; 5.64, 1H, d; 7.07, 1H, s; 7.98, 1H s; 8.54, 2H, s.].

REFERENCE EXAMPLE 41

Diisopropyl azodicarboxylate (0.97 mL) is added to a solution oftriphenylphosphine (1.29 g) in tetrahydrofuran (10 mL) while cooling to0-5° C. After stirring for 45 minutes methyl5-hydroxy-6-methoxynicotinoate (0.9 g) followed by a solution of(±)-endo(8,9,10-trinorbornan-2-ol) (0.552 g) in tetrahydrofuran (5 mL)are added and the mixture refluxed for 18 hours. Water is added and themixture is extracted with ethyl acetate, the extracts dried (MgSO₄) andevaporated to give a yellow oil. The oil is purified by flashchromatography (n-pentane/ethyl acetate 9:1 v/v on silica) to givemethyl (±)-6-methoxy-5-endo(8,9,10-trinorbornan-2-yloxy)nicotinoate,(1.1 g) as a white solid, m.p. 65-7° C. [Elemental analysis: —C, 64.90;H, 7.00; N, 4.95%. calculated: —C, 64.97; H, 6.91; N, 5.05%.]

REFERENCE EXAMPLE 42

Potassium hydroxide (380 mg) in water (5 mL) is added to a solution ofmethyl (±)-6-methoxy-5-endo(8,9,10-trinorbornan-2-yloxy)nicotinoate (1.1g) in methanol (30 mL) and the mixture stirred for 4 hours. Afterconcentrating, the residue is dissolved in water and the solutionacidified with concentrated aqueous hydrochloric acid. The product isextracted into ethyl acetate, the extracts dried (MgSO₄) and evaporatedto give (±)-6-methoxy-5-endo(8,9,10-trinorbornan-2-yloxy)nicotinic acid(0.95 g) as a white solid, m.p. 192-3° C.

[Elemental analysis: —C, 63.5; H, 6.36; N, 5.34%. calculated: —C, 63.86;H, 6.51; N, 5.32%.]

REFERENCE EXAMPLE 43

Diisopropyl azodicarboxylate (3.14 mL) is added to a mixture oftriphenylphosphine (4.19 g), 5-methoxy-2-trityloxymethyl-4-pyridone (5g) and (±)-tricyclo[2.2.1.0.^(2.6).]heptan-2-ol (1.43 g) in dry toluene(60 mL) at 10-15° C. under a nitrogen atmosphere. The mixture is stirredfor 30 minutes then heated at 60±5° C. for 24 hours. After cooling thesolvent is evaporated and the residue partitioned between water andethyl acetate. The ethyl acetate phase is washed with water then brineand dried (MgSO₄). Evaporation gives a brown oil which is purified byflash chromatography (n-pentane/ethylacetate 9:1 v/v as eluent onneutral alumina) to give(±)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6).]hept-2-yloxy)-2-trityloxymethylpyridine,(2.74 g), as a white solid, m.p. 140-2° C.

[Elemental analysis: —C, 80.70; H, 6.41; N, 2.54%. calculated: —C,80.95; H, 6.38; N, 2.86%.]

REFERENCE EXAMPLE 44

A solution of(±)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6).]hept-2-yloxy)-2-trityloxymethylpyridine(17 g) in glacial acetic acid is stirred at 65±5° C. for 24 hours. Aftercooling the solvent is removed in vacuo, the residue treated with waterand the resulting mixture extracted with ethyl acetate. The ethylacetate extracts are washed with 1 M aqueous hydrochloric acid, theaqueous washings basefied to pH 8 with 6 M aqueous sodium hydroxide andextracted with ethyl acetate. These extracts are dried (MgSO₄) andevaporated to give(±)-2-hydroxymethyl-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6).]hept-2-yloxy)pyridineas a colourless oil.

REFERENCE EXAMPLE 45

Sodium hydroxide (1.1 g) is added to a suspension of(±)-2-hydroxymethyl-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6).]hept-2-yloxy)pyridine(4.54 g) in water (70 mL). Activated manganese dioxide (9 g) is addedportionwise during 45 minutes and the resulting mixture heated at 65±5°C. for 6 hours. The mixture is filtered hot through diatomaceous earthand the filtrate concentrated to low volume in vacuo. The mixture isacidified with glacial acetic acid and extracted with dichloromethane.The extracts are dried (MgSO₄) and evaporated. The residue is purifiedby flash chromatography (ethyl acetate/methanol 19:1 v/v as eluent onsilica) to give(±)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6).]hept-2-yloxy)pyridine-2-carboxylicacid as a solid, m.p. 182-3° C.

REFERENCE EXAMPLE 46

A mixture of(±)-5-methoxy-4-(tricyclo[2.2.1.0.^(2.6).]hept-2-yloxy)pyridine-2-carboxylicacid (4.3 g) and concentrated hydrochloric acid (5 mL) in methanol (50mL) is refluxed for 8 hours. After cooling the mixture is concentratedto a low volume, diluted with water and neutralised with solid sodiumbicarbonate. The mixture is filtered and extracted with dichloromethane.The combined extracts are washed with saline, dried (MgSO₄) andevaporated to give (±)-methyl5-methoxy-4-(tricyclo[2.2.1.0.^(2.6).]hept-2-yloxy)pyridine-2-carboxylate(2.3 g). [¹Hnmr in D₆-DMSO shifts relative to Me₄Si:— 1.29, 2H, m; 1.47,3H, m; 1.60, 1H, d; 1.78, 1H, d; 2.14, 1H, br.s; 3.84, 3H, s; 3.94, 3H,s; 4.59, 1H, br.s; 7.67, 1H, s; 8.28, 1H, s.]

REFERENCE EXAMPLE 47

4-Dimethylaminopyridine (17.55 g) and trityl chloride (40.5 g) are addedto a solution of 5-benzyloxy-2-hydroxymethyl-4-pyridone (30.2 g) in drydimethylformamide and the mixture stirred and heated at 95° C. for 2hours. After cooling the mixture is poured into iced-water (800 mL) andthe precipitate collected, washed with water (2×500 mL) and sucked dry.The solid is boiled with methanol (500 mL) and after cooling the solidis collected, washed with methanol (200 mL) and diethyl ether (2×100 mL)and dried at 80° C. to give 5-benzyloxy-2-trityloxymethyl-4-pyridone(26.5 g) as a white solid, m.p. 233-5° C.

REFERENCE EXAMPLE 48

Diisopropyl azodicarboxylate (13.5 mL) is added to a mixture oftriphenylphosphine (18.15 g), 5-benzyloxy-2-trityloxymethyl-4-pyridone(21.1 g) and cyclopentanol (6.25 mL) in dry tetrahydrofuran (600 mL) at10-15° C. under a nitrogen atmosphere. The mixture is stirred for 30minutes then heated at reflux for 24 hours. After cooling the solvent isevaporated to give a brown oil which is purified by flash chromatography(n-pentane/ethyl acetate 4:1 v/v as eluent on silica) to give5-benzyloxy-4-cyclopentyloxy-2-trityloxymethylpyridine as a colourlessoil.

REFERENCE EXAMPLE 49

5% Palladium on charcoal catalyst (2 g) is added to a solution of5-benzyloxy-4-cyclopentyloxy-2-trityloxymethylpyridine (24.2 g) inethanol (500 mL) and the mixture stirred at room temperature under ahydrogen atmosphere for 3 hours. After filtering the filtrate isconcentrated in vacuo to give a colourless oil which is purified byflash chromatography (n-pentane/ethyl acetate 7:3 v/v as eluent onsilica) to give 4-cyclopentyloxy-5-hydroxy-2-trityloxymethylpyridine(18.8 g) as a colourless foam. [¹Hnmr in deuterochloroform with Me₄Si asstandard:— 1.70, 2H, m; 1.82, 2H, m; 1.90-2.08, 4H, m; 4.25, 2H, s;4.93, 1H, m; 7.19, 1H, s; 7.24, 7.30, 7.49, 15H, Ar; 8.04, 1H, s.].

REFERENCE EXAMPLE 50

Chlorodifluoromethane is bubbled through a suspension of potassiumcarbonate (2.13 g) and potassium iodide (584 mg) in a solution of4-cyclopentyloxy-5-hydroxy-2-trityloxymethylpyridine (5 g) indimethylformamide (40 mL) while heating at 70±5° C. and using acardice/acetone condenser to recycle the condensate. After 4 hours theaddition of chlorodifluoromethane is stopped and the mixture heated fora further 16 hours. After cooling the mixture is concentrated in vacuo,the residue diluted with water, acidified to pH 4 with glacial aceticacid and extracted with dichloromethane. The extracts are dried (MgSO₄)and evaporated. The residue is purified by flash chromatography(gradient elution using n-pentane/ethyl acetate 9:1 v/v to 7:3 v/v onsilica) to give4-cyclopentyloxy-5-difluoromethoxy-2-trityloxymethylpyridine (240 mg) asan oil.

[¹Hnmr in deuterochloroform with Me₄Si as standard:— 1.72, 2H, m; 1.85,2H, m; 2.00, 4H, m; 4.31, 2H, s; 4.95, 1H, m; 6.51, 1H, t, J=74 Hz;7.22-7.55, 16H, m; 8.19, 1H, s.].

REFERENCE EXAMPLE 51

A mixture of 5,6-dimethoxy-3-methylpyridazine-2-oxide (0.5 g) in aceticanhydride (2 mL) is refluxed for 2 hours. After cooling the mixture isdiluted with water and extracted with ethyl acetate (2×20 mL). Theextracts are dried (MgSO₄) and evaporated to give a brown oil which ispurified by flash chromatography (ethyl acetate as eluent on silica) togive 6-acetoxymethyl-3,4-dimethoxypyridazine (0.27 g) as a colourlessoil.

REFERENCE EXAMPLE 52

A solution of potassium carbonate (0.2 g) in water 2 mL) is added to asolution of 6-acetoxymethyl-3,4-dimethoxypyridazine (0.27 g) in methanol(6 mL) and the mixture stirred at 60-70° C. for 2 hours. Afterevaporating to dryness the residue is partitioned between ethyl acetate(10 mL) and brine (10 mL). The ethyl acetate phase is evaporated todryness and the residue purified by flash chromatography (ethyl acetateas eluent on silica) to give 3,4-dimethoxy-6-hydroxymethylpyridazine asa white solid, m.p. 151-3° C.

REFERENCE EXAMPLE 53

A solution of oxalyl chloride (0.61 mL) in dichloromethane (11 mL) iscooled to −60° C. and dimethylsulphoxide (0.98 g) is added dropwisemaintaining the reaction mixture at −60° C. After 15 minutes a solutionof 3,4-dimethoxy-6-hydroxymethylpyridazine (1.0 g) in dichloromethane(42 mL) is added dropwise during 45 minutes maintaining the reactionmixture at −60° C. After a further 15 minutes triethylamine (3.96 mL) isadded, the mixture stirred at −60° C. for 15 minutes then cooling isdiscontinued. When the reaction mixture attains room temperaturestirring is continued for 1 hour. The reaction mixture is diluted withwater (100 mL) and dichloromethane (100 mL) and the organic phaseseparated. The aqueous phase is re-extracted with dichloromethane (100mL) and the combined extracts are dried (MgSO₄). Evaporation gave5,6-dimethoxypyridazine-3-carboxaldehyde (0.95 g) as a white solid, m.p.179-81° C.

REFERENCE EXAMPLE 54

n-Butyllithium (1.51 mL of a 1.6 M solution in hexane) is added to asolution of diisopropylamine (0.34 mL) in tetrahydrofuran (29 mL) at−10° C. under a nitrogen atmosphere. After 30 minutes the mixture iscooled to −70° C. and a solution of 3,5-dichloro-4-methylpyridine (0.39g) in tetrahydrofuran (4 mL) is added dropwise. After 30 minutes asolution of 5,6-dimethoxy-pyridazine-3-carboxaldehyde (0.35 g) intetrahydrofuran (15 mL) is added at −70 to −60° C. and stirringcontinued at this temperature for 1 hour before cooling is discontinued.After 24 hours the yellow solution is quenched by the addition ofaqueous ammonium chloride and the mixture extracted with ethyl acetate.The dried extracts (MgSO₄) are evaporated and the residue purified byflash chromatography (ethyl acetate as eluent on silica) to give(±)-2-(3,5-dimethylpyrid-4-yl)-1-(5,6-dimethoxypyridazin-3-yl)ethanol(0.17 g), as a white solid, m.p. 217-8° C.

REFERENCE EXAMPLE 55

Water (4 drops is added to a solution of4-cyclopentyloxy-5-difluoromethoxy-2-trityloxypyridine (900 mg) inglacial acetic acid (20 mL) and the mixture heated at 60° C. for 18hours. After cooling the mixture is evaporated to dryness and theresidue partitioned between water and ethyl acetate. The organic phaseis dried over magnesium sulphate and evaporated to give a pale yellowsolid which is purified by flash chromatography (gradient elution usingn-pentane/ethyl acetate 7:3 v/v to n-pentane/ethyl acetate 2:3 v/v onsilica) to give4-cyclopentyloxy-5-difluoromethoxy-2-hydroxymethylpyridine (250 mg) as awhite solid, m.p. 85-6° C.

REFERENCE EXAMPLE 56

Solid potassium permanganate (306 mg) is added portionwise to a stirredsuspension of 4-cyclopentyloxy-5-difluoromethoxy-2-hydroxymethylpyridine(250 mg) in water (10 mL) while heating at 50±5° C. The resultingmixture is heated for 1.5 hours at this temperature, then at 70° C. forminutes. A solution of potassium hydroxide (150 mg) in water (1 mL) isadded followed by the addition of isopropanol until the excess potassiumpermanganate is consumed. After 15 minutes, the mixture is cooled andfiltered through a pad of diatomaceous earth and the filtrate adjustedto pH 5 with glacial acetic acid. The white precipitate is collected,washed with water and dried in vacuo to give4-cyclopentyloxy-5-difluoromethoxypyridine-2-carboxylic acid (240 mg) asa white solid, m.p. 215-6° C. decomp. [Elemental analysis: —C, 52.57; H,4.67; N, 5.18%. calculated: —52.75; H, 4.80; N, 5.13%].

The compounds of formula I exhibit useful pharmacological activity andaccordingly are incorporated into pharmaceutical compositions and usedin the treatment of patients suffering from certain medical disorders.More especially, they are cyclic AMP phosphodiesterase inhibitors, inparticular type IV cyclic AMP phosphodiesterase inhibitors. The presentinvention provides compounds of formula I, and compositions containingcompounds of formula I, which are of use in a method for the treatmentof a patient suffering from, or subject to, conditions which can beameliorated by the administration of an inhibitor of cyclic AMPphosphodiesterase. For example, compounds within the present inventionare useful as bronchodilators and asthma-prophylactic agents and agentsfor the inhibition of eosinophil accumulation and of the function ofeosinophils, such as for the treatment of inflammatory airways disease,especially reversible airway obstruction or asthma, and for thetreatment of other diseases and conditions characterized by, or havingan etiology involving, morbid eosinophil accumulation. As furtherexamples of conditions which can be ameliorated by the administration ofinhibitors of cyclic AMP phosphodiesterase such as compounds of formulaI there may be mentioned inflammatory diseases, such as a topicdermatitis, urticaria, allergic rhinitis, psoriasis, rheumaticarthritis, ulcerative colitis, Crohn's disease, adult respiratorydistress syndrome and diabetes insipidus, other proliferative skindiseases such as keratosis and various types of dermatitis, conditionsassociated with cerebral metabolic inhibition, such as cerebralsenility, multi-infarct dementia, senile dementia (Alzheimer's disease),and memory impairment associated with Parkinson's disease, andconditions ameliorated by neuroprotectant activity, such as cardiacarrest, stroke, and intermittent claudication. A special embodiment ofthe therapeutic methods of the present invention is the treating ofasthma.

The compounds are also inhibitors of tumor necrosis factor, especiallya-TNF. Thus, the present invention provides compounds of formula I, andcompositions containing compounds of formula I, which are of use in amethod for treating a patient suffering from, or subject to, conditionswhich can be ameliorated by the administration of an inhibitor of a-TNF.For example compounds of the present invention are useful in jointinflammation, arthritis, rheumatoid arthritis and other arthriticconditions such as rheumatoid spondylitis and osteoarthritis.Additionally, the compounds are useful in treatment of sepsis, septicshock, gram negative sepsis, toxic shock syndrome, acute respiratorydistress syndrome, asthma and other chronic pulmonary diseases, boneresorption diseases, reperfusion injury, graft vs. host reaction andallograft rejection. Furthermore, the compounds are useful in thetreatment of infections such as viral infections and parasiticinfections, for example malaria such as cerebral malaria, fever andmyalgias due to infection, HIV, AIDS, cachexia such as cachexiasecondary to AIDS or to cancer. Other disease states that may be treatedwith the compounds of the present invention include Crohn's disease,ulcerative colitis, pyresis, systemic lupus erythematosus, multiplesclerosis, type I diabetes mellitus, psoriasis, Beçhet's disease,anaphylactoid purpura nephritis, chronic glomerulonephritis,inflammatory bowel disease and leukemia. A special embodiment of thetherapeutic methods of the present invention is the treating of jointinflammation.

According to a further feature of the invention there is provided amethod for the treatment of a human or animal patient suffering from, orsubject to, conditions which can be ameliorated by the administration ofan inhibitor of cyclic AMP phosphodiesterase or of TNF, especiallya-TNF, for example conditions as hereinbefore described, which comprisesthe administration to the patient of an effective amount of compound offormula I or a composition containing a compound of formula I.“Effective amount” is meant to describe an amount of compound of thepresent invention effective in inhibiting cyclic AMP phosphodiesteraseand/or TNF and thus producing the desired therapeutic effect.

The present invention also includes within its scope pharmaceuticalformulations which comprise at least one of the compounds of formula Iin association with a pharmaceutically acceptable carrier or coating.

In practice compounds of the present invention may generally beadministered parenterally, rectally or orally, but they are preferablyadministered by inhalation.

The products according to the invention may be presented in formspermitting administration by the most suitable route and the inventionalso relates to pharmaceutical compositions containing at least oneproduct according to the invention which are suitable for use in humanor veterinary medicine. These compositions may be prepared according tothe customary methods, using one or more pharmaceutically acceptableadjuvants or excipients. The adjuvants comprise, inter alia, diluents,sterile aqueous media and the various non-toxic organic solvents. Thecompositions may be presented in the form of tablets, pills, granules,powders, aqueous solutions or suspensions, injectable solutions, elixirsor syrups, and can contain one or more agents chosen from the groupcomprising sweeteners, flavorings, colorings, or stabilizers in order toobtain pharmaceutically acceptable preparations.

The choice of vehicle and the content of active substance in the vehicleare generally determined in accordance with the solubility and chemicalproperties of the product, the particular mode of administration and theprovisions to be observed in pharmaceutical practice. For example,excipients such as lactose, sodium citrate, calcium carbonate, dicalciumphosphate and disintegrating agents such as starch, alginic acids andcertain complex silicates combined with lubricants such as magnesiumstearate, sodium lauryl sulfate and talc may be used for preparingtablets. To prepare a capsule, it is advantageous to use lactose andhigh molecular weight polyethylene glycols. When aqueous suspensions areused they can contain emulsifying agents or agents which facilitatesuspension. Diluents such as sucrose, ethanol, polyethylene glycol,propylene glycol, glycerol and chloroform or mixtures thereof may alsobe used.

For parenteral administration, emulsions, suspensions or solutions ofthe products according to the invention in vegetable oil, for examplesesame oil, groundnut oil or olive oil, or aqueous-organic solutionssuch as water and propylene glycol, injectable organic esters such asethyl oleate, as well as sterile aqueous solutions of thepharmaceutically acceptable salts, are used. The solutions of the saltsof the products according to the invention are especially useful foradministration by intramuscular or subcutaneous injection. The aqueoussolutions, also comprising solutions of the salts in pure distilledwater, may be used for intravenous administration with the proviso thattheir pH is suitably adjusted, that they are judiciously buffered andrendered isotonic with a sufficient quantity of glucose or sodiumchloride and that they are sterilized by heating, irradiation ormicrofiltration.

Suitable compositions containing the compounds of the invention may beprepared by conventional means. For example, compounds of the inventionmay be dissolved or suspended in a suitable carrier for use in anebulizer or a suspension or solution aerosol, or may be absorbed oradsorbed onto a suitable solid carrier for use in a dry powder inhaler.

Solid compositions for rectal administration include suppositoriesformulated in accordance with known methods and containing at least onecompound of formula I.

The percentage of active ingredient in the compositions of the inventionmay be varied, it being necessary that it should constitute a proportionsuch that a suitable dosage shall be obtained. Obviously, several unitdosage forms may be administered at about the same time. The doseemployed will be determined by the physician, and depends upon thedesired therapeutic effect, the route of administration and the durationof the treatment, and the condition of the patient. In the adult, thedoses are generally from about 0.001 to about 50, preferably about 0.001to about 5, mg/kg body weight per day by inhalation, from about 0.01 toabout 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg bodyweight per day by oral administration, and from about 0.001 to about 10,preferably 0.01 to 1, mg/kg body weight per day by intravenousadministration. In each particular case, the doses will be determined inaccordance with the factors distinctive to the subject to be treated,such as age, weight, general state of health and other characteristicswhich can influence the efficacy of the medicinal product.

The products according to the invention may be administered asfrequently as necessary in order to obtain the desired therapeuticeffect. Some patients may respond rapidly to a higher or lower dose andmay find much weaker maintenance doses adequate. For other patients, itmay be necessary to have long-term treatments at the rate of 1 to 4doses per day, in accordance with the physiological requirements of eachparticular patient. Generally, the active product may be administeredorally 1 to 4 times per day. It goes without saying that, for otherpatients, it will be necessary to prescribe not more than one or twodoses per day.

Compounds within the scope of the present invention exhibit markedpharmacological activities according to tests described in theliterature which tests results are believed to correlate topharmacological activity in humans and other mammals. The followingpharmacological test results are typical characteristics of compounds ofthe present invention.

1. Inhibitory Effects of Compounds on PDE Activity.

1.1 Preparation of PDE Isozymes from Pig Aorta.

The method is described fully by Souness and Scott (Biochem. J., 291,389-395, 1993). Briefly, aortas of freshly slaughtered pigs are placedin Hepes buffered krebs solution, extraneous tissue on the outside ofthe aorta is trimmed off and the endothelial layer on the intimalsurface is removed by rubbing with a cotton swab. Smooth muscle stripsare plucked from the aorta and 25 g are homogenized using a WaringBlender in homogenization buffer (20 mM Tris/HCl, pH 7.5, 2 mM MgCl₂, 1mM dithiothreitol, 5 mM EDTA and 1 mg/ml aprotinin). The homogenate isfurther homogenized with an Ultra-Turrax and then centrifuged (3000 g, 5minutes). The supernatant is removed, and the pellet is sonicated in asmall volume (25-50 mL) of homogenization buffer. The sonicate iscentrifuged (3000 g, 5 minutes), the pellet discarded and thesupernatant is pooled with that from the first centrifugation step. Thepooled supernatants are centrifuged (100,000 g, 1 hour), the resultinghigh-speed supernatant is filtered (0.45 μm) and then applied to aDEAE-trisacryl (IBF) column (50×2.44 cm) preequilibrated in columnbuffer (20 mM Tris/HCl, pH 7.5, 2 mM MgCl₂, 1 mM dithiothreitol, 20 μMTLCK). The column is washed with 500-700 mL of column buffer and PDEactivities are eluted with 2 successive linear gradients of NaCl (0-200mM, 400 mL and 200-300 mM, 200 mL) in column buffer. The fractions inthe separated peaks of activity corresponding to the different PDEisozymes are pooled and stored at −20° C. in 30% (v/v) ethylene glycol.

1.2 Measurement of PDE Activity.

PDE activity is determined by the two-step radioisotopic method ofThompson et al., Adv. Cyclic Nucl. Res., 10, 69-92 (1979). The reactionmixture contains 20 mM Tris/HCl (pH 8.0), 10 mM MgCl₂, 4 mM2-mercaptoethanol, 0.2 mM EGTA and 0.05 mg of BSA/mL. The concentrationof substrate is 1 μM.

The IC₅₀ values for the compounds examined are determined fromconcentration-response curves in which concentrations range from 0.1nM-to 40 μM.

1.3 Results.

Compounds within the scope of the invention produce up to about 50%inhibition of porcine aortic cyclic AMP-specific phosphodiesterase (PDEIV) at concentrations from about 10⁻⁹ M up to about 10⁻⁵ M, preferablyfrom about 10⁻⁹ up to about 10⁻⁸ M. The compounds of the invention arefrom about 10,000-fold to about 50-fold more selective for cyclic AMPphosphodiesterase IV than cyclic nucleotide phosphodiesterase types I,III or V.

2. Inhibitory Effects of Compounds on Eosinophil Superoxide Generation.

2.1 Preparation of Guinea-pig Eosinophils.

The method is described fully in Souness et al (Biochem. Pharmacol. 42,937-945, 1991).

2.2 Measurement of Superoxide Generation.

Superoxide anion generation is determined as the superoxide dismutaseinhibitable reduction of p-iodonitrotetrazolium violet (INTV) (Sounesset al, Biochem. Pharmacol. 42, 937-945, 1991). Briefly, cells areincubated in 96 well microtitre plates in 0.25 mL of Hanks buffered saltsolution (HBSS) containing INTV (0.5 mg/mL) plus other additions for 45minutes at 37° C. The cells are then centrifuged at 500 g for 5 minutesand the supernatant is aspirated. The pellet is solubilized byincubation overnight at room temperature in DMSO containing 0.6 M HCland the absorbance of the reduced dye is measured at 492 nm. The resultsare expressed in absorbance units.

2.3 Results.

Compounds within the scope of the invention produce up to about 50%inhibition of superoxide generation from eosinophiis harvested from theperitoneal cavities of guinea-pigs at concentrations from about 10⁻⁸ Mto about 10⁻⁵ M, preferably from about 10⁻⁸ M up to about 10⁻⁷ M.

3. Effects of Compounds on Tracheal Smooth Muscle Contractility.

3.1 Preparation of Guinea-pig Tracheal Strips and Contractility Studies.

Organ bath studies are performed essentially according to Tomkinson etal (Br. J. Pharmacol. 108 57-61, 1993). Briefly, tracheas are removedfrom male, Dunkin-Hartley guinea-pigs (400-500 g) are placed in KrebsRinger Bicarbonate (KRB) solution and fat and connective tissue aredissected away. Epithelium is removed by mechanical abrasion and thetracheal strips are suspended under an applied load, such that they areat their optimal length, derived from preliminary experiments, andequilibrated for 90 minutes, washing at 15 minute intervals.

Cumulative concentration-response curves to spasmogens are constructedand the concentration producing 30% of maximum contraction (EC₃₀) isdetermined by computerized linear regression analysis. For relaxantstudies, tissues are contracted with spasmogens (such as methacholine,histamine, leukotriene D₄) (EC₃₀) and when the response plateaus, PDEinhibitors (10 nM-100 μM) or vehicle control (DMSO) are addedcumulatively. The concentration of relaxant producing 50% inhibition(IC₅₀) of the agonist response is calculated by linear regression.Alternatively, PDE inhibitors, as above, may be added to tissues underbasal tone and the concentration producing 50% relaxation (EC₅₀)calculated as above.

3.2 Results.

Compounds within the scope of the invention produce about 50% relaxationof guinea-pig tracheal strips (under basal tone or which had beencontracted by treatment with spasmogens) at concentrations from about5×10⁻⁹ M to about 10⁻⁵ M, preferably from about 5×10⁻⁹ M to about 10⁻⁷M.

4. In vivo Bronchodilator Actions of Compounds.

4.1 Measurement of Bronchodilatation.

Bronchorelaxant activity is measured in in vivo tests in theanaesthetized guinea-pig or rat according to the method described inUnderwood et al., Pulm. Pharmacol. 5, 203-212, (1992) in which theeffects on bronchospasm induced by histamine (or other spasmogens suchas methacholine or leukotriene D₄) is determined. Nebulized aerosolsgenerated from aqueous solutions of compounds of the invention are eachadministered for one minute to the anaesthetized animals. Alternatively,dry powder formulations made up from compounds of the invention andlactose are blown into the airways of the anaesthetized guinea-pigs orrats by the method described in Underwood et al., J. Pharm. Methods, 26,203-210, 1991.

4.2 Results.

Compounds within the scope of the invention produce from about 30% up toabout 90% decrease in bronchospasm when administered at effective dosesof about 4 to about 1000 μg/kg, preferably about 4 to about 50 μg/kg,without any significant effect on blood pressure.

5. In vivo Actions of Compounds on Antigen (Ovalbamin)-inducedEosinophilia in Guinea-pigs.

5.1 Treatment of Animals and Measurement of Eosinophil Numbers.

Male Dunkin-Hartley guinea-pigs weighing 200-250 g are sensitized using10 μg ovalbumin in 1 mL of a 100 mg/mL suspension of aluminiumhydroxide, i.p.

Sensitized guinea-pigs are anaesthetised and dry powder formulations ofPDE inhibitors or lactose are administered (i.t.) into the airways. Insome cases PDE inhibitors are administered orally. 23 hours later theprocedure is repeated and 60 minutes later the guinea-pigs arechallenged with nebulised saline or ovalbumin (1% in saline) for 15seconds. 24 hours after challenge the guinea-pigs are killed and thelungs are lavaged with warm saline. Total and differential cell countsare made.

5.2 Results.

Compounds within the scope of the invention, administered one hourbefore challenge, inhibit by at least 50% ovalbumin-induced eosinophiliain guinea-pigs which is measured 24 hours after challenge, at oral dosesof about 1 to about 50 mg/kg, preferably about 1 to 10 mg/kg and inhaleddoses of about 4 to 1000 μg/kg, preferably 4 to 50 μg/kg.

6 In Vitro Inhibitory Effects on TNF-alpha Release by Human Monocytes.

The effects of compounds on TNF-alpha production by human peripheralblood monocytes (PBMs) are examined as follows:

6.1. Preparation of Blood Leukocytes.

Blood is drawn from normal donors, mixed with dextran, and theerythrocytes allowed to sediment for 35 minutes at 37° C. Leukocytes arefractionated by centrifugation through a discontinuous (18, 20 and 22%)metrizamide gradient. The mononuclear cell fraction comprising 30-40%PBMs is suspended in HBSS and stored at 4° C. until use.

6.2. Measurement of TNF-alpha.

Cells from the PBM-rich metrizamide fraction are spun down (200 g for 10minutes at 20° C.), resuspended at 106 PBMs/mL of medium; RPMI 1640containing 1% v/v FCS, 50 U/mL penicillin and 50 mg/mL streptomycin(Gibco, U.K.), then plated out in 96 well plates at 2×10⁵ cells/well.The medium (200 μL) is changed to remove any non-adherent cells and theremaining, adherent PBMs left in the incubator overnight (18 hours). Onehour prior to challenge, the medium is changed to that containingcompound for test or drug vehicle. Control treatments and compounds fortest are assayed in quadruplicate wells. Compounds are tested within theconcentration range of 3×10⁻¹⁰ M to 3×10⁻⁶ M. Medium (50 μL) with orwithout 10 ng/ml LPS (E. Coli, 055 B5 from Sigma, U.K.) is then added.The incubation is then continued for a further 4 hours. Cellsupernatants are removed for storage at −20° C.

TNFa levels in cell supernatants are quantified using a standardsandwich ELISA technique. ELISA plates (Costar, U.K.) are coatedovernight at 4° C. with 3 mg/mL polyclonal goat anti-human TNF-alphaantibody (British Biotechnology, U.K.) in pH 9.9 bicarbonate buffer.Rabbit polyclonal anti-human TNF-alpha antiserum (Janssen Biochimicha,Belgium) at 1/500 dilution is used as the second antibody and polyclonalgoat anti-rabbit IgG horseradish peroxidase (Calbiochem, U.S.A.) at1/8000 dilution is used as the detection antibody. Color development ismeasured by absorbance at 450 nm using a Titek plate reader.

TNF-alpha levels are calculated by interpolation from a standard curveusing recombinant human TNF-alpha (British Biotechnology U.K.)(0.125-8ng/mL). Data (log-conc. vs. log-resp) are fitted by linear regression(p>0.99) using a Multicalc (Wallac Pharmacia, U.K.) software program.Basal TNF-alpha levels are less than 100 pg/mL whilst LPS stimulation ofthe PBMs increases TNF-alpha levels to 3-10 ng/mL.

6.3 Results.

Compounds within the scope of the invention produce 50% inhibition ofLPS-induced TNF-alpha release from human PBMs at concentrations withinthe range of about 10⁻⁹ M to about 10⁻⁶ M., preferably about 10⁻⁹ M toabout 10⁻⁸ M.

7. Inhibitory Effects of Compounds on Antigen-inducedBronchoconstriction in the Conscious Guinea-pig.

7.1. Sensitisation of Guinea-pigs and Measurement of Antigen—InducedBronchoconstriction.

Male, Dunkin-Hartley guinea-pigs (550-700 g) are sensitized as above.Specific airways resistance (SRaw) is measured in conscious animals bywhole body plethysmography using a variation of the method of Pennock etal., (J. Appl. Physiol., 46, 399, 1979). Test compounds or vehicle(lactose carrier) are instilled into the airways as dry powders througha metal gavage needle. 30 minutes later, the animals are injected withmepyramine (30 mg/kg i.p.) to prevent anaphylactic collapse and placedinto the plethysmography chambers where SRaw is determined at 1 minuteintervals. Resting SRaw is then determined. Animals are challenged withan aerosol of ovalbumin and SRaw is determined every 5 minutes for 15minutes.

7.2. Results.

Compounds within the scope of the invention inhibit antigen-inducedbronchoconstriction by up to 80% at doses of between about 1 to about1000 μg/kg (i.t.), preferably about 1 to about 20 μg/kg (i.t.).

8. Inhibitory Effects of Compounds on Serum TNF-Alpha Levels inLPS-challenged Mice.

8.1. Treatment of Animals and Measurement of Murine TNF-alpha.

Female Balb/c mice (age 6-8 weeks, weight 20-22 g from Charles River,U.K.) in groups of five or more animals are dosed p.o. with compoundssuspended in 1.5% (w/v) carboxymethyl cellulose then challenged after aminimum period of 30 min with 30 mg of LPS i.p. After 90 min the animalsare killed by CO₂ asphyxiation and bled by cardiac puncture. Blood isallowed to clot at 4° C., centrifuged (12,000 g for 5 minutes) and serumtaken for TNF-alpha analysis.

TNF-alpha levels are measured using a commercially available murineTNF-alpha ELISA kit, purchased from Genzyme (Cat. no. 1509.00), asrecommended by the manufacturer. Values for TNF-alpha are calculatedfrom a recombinant murine TNF-alpha standard curve.

8.2 Results.

Compounds within the scope of the invention inhibit LPS-induced serumTNF-alpha at doses between about 10 and about 10,000 mg/kg, preferablyabout 10 to about 250 μg/kg.

The value of the compounds of the invention is enhanced by their verylow mammalian toxicity levels.

The following Composition Examples illustrate pharmaceuticalcompositions according to the present invention.

COMPOSITION EXAMPLE 1

N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxy-benzamide(1.0 g) (mean particle size 3.5 microns) and lactose (99 g) (meanparticle size 72 microns) are blended together for 30 minutes in amechanical shaker/mixer. The resulting blend is filled, to a fill weightof 25 mg, into No. 3 hard gelatine capsules, to give a product suitablefor use, for example, with a dry powder inhaler.

COMPOSITION EXAMPLE 2

No. 2 size gelatin capsules each containing:-N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy- 20 mg6-fluoro-4methoxybenzamide lactose 100 mg  starch 60 mg dextrin 40 mgmagnesium stearate  1 mg are prepared in accordance with the usualprocedure.

COMPOSITION EXAMPLE 3

5-Cyclopentyloxy-N-(3,5-dichloropyrid-4-yl)-6-methoxynicotinamide (1.0g) (mean particle size 3.5 microns) and lactose (99 g) (mean particlesize 72 microns) are blended together for 30 minutes in a mechanicalshaker/mixer. The resulting blend is filled, to a fill weight of 25 mg,into No. 3 hard gelatine capsules, to give a product suitable for use,for example, with a dry powder inhaler.

COMPOSITION EXAMPLE 4

No. 2 size gelatin capsules each containing:-5-cyclopentyloxy-N-(3,5-dichloro-pyrid-4-yl)- 20 mg6-methoxynicotinamide lactose 100 mg  starch 60 mg dextrin 40 mgmagnesium stearate  1 mg are prepared in accordance with the usualprocedure.

Compositions similar to those above are prepared from other compounds offormula I.

1. A compound of formula XIX

wherein R¹ is C₁₋₄ alkyl optionally substituted by one or more of halo,cycloalkyl or cycloalkenyl; R² is alkyl, alkenyl or alkynyl eachoptionally substituted by one or more of halo, cycloalkyl orcycloalkenyl; or cycloalkyl or cycloalkenyl each optionally substitutedby one or more of halo, methylidene or alkyl; or optionally substitutedcyclothioalkyl consisting of a non-aromatic monocyclic or multicyclicring system of 3 to about 10 ring atoms wherein at least one of the ringatoms is sulfur and the other ring atoms are carbon and the substitutedcyclothioalkyl is substituted by one or more halo, or any ring sulfuratom is optionally oxidized to the corresponding S-oxide or S,S-dioxide;or optionally substituted cyclothioalkenyl consisting of a non-aromaticmonocyclic or multicyclic ring system of 3 to about 10 ring atomswherein at least one of the ring atoms is sulfur, the other ring atomsare carbon and the ring system contains a carbon-carbon double bond andthe substituted cyclothioalkenyl is substituted by one or more halo orany ring sulfur atoms is optionally oxidized to the correspondingS-oxide or S,S-dioxide; Q¹, Q² and Q³ are independently nitrogen, CX orCH, provided that at least one of Q¹, Q² and Q³ is other than CH; Z¹ andZ² are independently oxygen or sulfur; and X is halo; provided that Z1amd Z2 are not both sulfur.
 2. The compound of claim 1 wherein one ofQ¹, Q² and Q³ is nitrogen.
 3. The compound of claim 2 wherein Q¹ is N,and Q² and Q³ are CH; or Q² is N, and Q¹ and Q³ are CH.
 4. The compoundof claim 3 wherein Q² is N, and Q¹ and Q³ are CH.
 5. The compound ofclaim 4 wherein: R¹ is C₁₋₄ alkyl; R² is alkyl, alkenyl or alkynyl eachoptionally substituted by one or more of halo or cycloalkyl; and Z¹ andZ² are both oxygen.
 6. The compound of claim 5 wherein: R² is alkylsubstituted by one or more cycloalkyl.
 7. The compound of claim 6wherein: R² is cyclopropylmethyl.
 8. A compound according to claim 1which is 4-cyclopropylmethoxy-5-methoxypyridine-2-carboxylic acid.